1
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Bak-Gordon P, Manley JL. SF3B1: from core splicing factor to oncogenic driver. RNA (NEW YORK, N.Y.) 2025; 31:314-332. [PMID: 39773890 DOI: 10.1261/rna.080368.124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 12/23/2024] [Indexed: 01/11/2025]
Abstract
Highly recurrent somatic mutations in the gene encoding the core splicing factor SF3B1 are drivers of multiple cancer types. SF3B1 is a scaffold protein that orchestrates multivalent protein-protein interactions within the spliceosome that are essential for recognizing the branchsite (BS) and selecting the 3' splice site during the earliest stage of pre-mRNA splicing. In this review, we first describe the molecular mechanism by which multiple oncogenic SF3B1 mutations disrupt splicing. This involves perturbation of an early spliceosomal trimeric protein complex necessary for accurate BS recognition in a subset of introns, which leads to activation of upstream branchpoints and selection of cryptic 3' splice sites. We next discuss how specific transcripts affected by aberrant splicing in SF3B1-mutant cells contribute to the initiation and progression of cancer. Finally, we highlight the prognostic value and disease phenotypes of different cancer-associated SF3B1 mutations, which is critical for developing new targeted therapeutics against SF3B1-mutant cancers still lacking in the clinic.
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Affiliation(s)
- Pedro Bak-Gordon
- Department of Biological Sciences, Columbia University, New York, New York 10027, USA
| | - James L Manley
- Department of Biological Sciences, Columbia University, New York, New York 10027, USA
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2
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Sun Y, Yu Y, Cai L, Yu B, Xiao W, Tan X, Wang Y, Lu Y, Wang N. Clonal hematopoiesis of indeterminate potential, health indicators, and risk of cardiovascular diseases among patients with diabetes: a prospective cohort study. Cardiovasc Diabetol 2025; 24:72. [PMID: 39948662 PMCID: PMC11827465 DOI: 10.1186/s12933-025-02626-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 02/03/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND Clonal hematopoiesis of indeterminate potential (CHIP) was associated with diabetes and cardiovascular diseases (CVD). However, the effect of CHIP on CVD have not been evaluated among patients with diabetes, and whether maintaining the healthy indictors could mitigate the adverse influence was also unclear. METHODS A total of 22,239 adults from the UK Biobank with diabetes and available whole-exome sequence data, and free of CVD were included. Multivariable-adjusted Cox regressions were used to explore the associations of any CHIP (variant allele fraction ≥ 2%), large CHIP (variant allele fraction ≥ 10%), and the top 10 commonly mutated driver genes for CHIP and with risk of CVD. The joint associations between health indicators (body mass index [BMI], HbA1c, blood pressure [BP], and low-density lipoprotein cholesterol [LDL]) and CHIP were further investigated. RESULTS Over a median follow-up of 13.2 years, 5366 participants with diabetes developed CVD events. The hazard ratios (HRs) (95% confidence intervals [CIs]) of any CHIP and large CHIP were (1.21, 1.08-1.36) and (1.25, 1.09-1.43) for incident CVD, respectively. Significant associations between any CHIP and coronary heart disease (HR, 95%CI: 1.18, 1.03-1.36) and heart failure (1.73, 1.46-2.06) were observed, but not for stroke (1.14, 0.89-1.48). Gene-specific analyses suggested that the greatest association were for SF3B1 (HR, 95%CI: 2.50, 1.25-5.01) and TET2 (HR, 95%CI: 1.36, 1.07-1.77) with risk of CVD. There was no significant interaction between the four health indicators and CHIP in relation to incident CVD. Compared to patients without CHIP, those with any CHIP and ideal health indicators still exhibited significantly or nonsignificantly higher HRs (BMI: 1.18, 0.82-1.68; HbA1c: 1.12, 0.96-1.30; BP: 1.24, 1.03-1.49; LDL: 1.29, 1.09-1.53). Similar results were demonstrated using large CHIP. CONCLUSIONS CHIP is independently associated with an increased risk of CVD in patients with diabetes, regardless of health indicator levels. Diabetic patients with CHIP but ideal health indicators still exhibited higher CVD risk compared with diabetic patients without CHIP.
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Affiliation(s)
- Ying Sun
- Department of Endocrinology and Metabolism, Institute of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Yuefeng Yu
- Department of Endocrinology and Metabolism, Institute of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Lingli Cai
- Department of Endocrinology and Metabolism, Institute of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Bowei Yu
- Department of Endocrinology and Metabolism, Institute of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Wenying Xiao
- Department of Cardiology, Shidong Hospital, University of Shanghai for Science and Technology, Shanghai, China
| | - Xiao Tan
- Department of Big Data in Health Science, Department of Psychiatry, Sir Run Shaw Hospital, Zhejiang University School of Public Health, Zhejiang University School of Medicine, Hangzhou, China
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Yu Wang
- Department of Cardiology, Shidong Hospital, University of Shanghai for Science and Technology, Shanghai, China.
| | - Yingli Lu
- Department of Endocrinology and Metabolism, Institute of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Ningjian Wang
- Department of Endocrinology and Metabolism, Institute of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
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3
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Harrison SJ, Touzeau C, Kint N, Li K, Nguyen T, Mayeur-Rousse C, Rahman M, Le Bris Y, Er J, Eugene-Lamer J, Haynes NM, Li J, Abbott RC, Bodet-Milin C, Moreau A, Letouzé E, Lendvai N, Schecter JM, Deraedt W, Banerjee A, Lengil T, Vogel M, Foulk B, Zhao H, Smirnov D, Slaughter A, Lonardi C, Lee E, Marquez L, Sankari A, Plaks V, Filho JOC, Patel N, Geng D, Gastinne T, Kelly H, Tiong IS, Eveillard M, Chevallier P, Lade S, Moreau P, Grimmond S, Oliaro J, Tessoulin B, Blombery P. CAR+ T-Cell Lymphoma after Cilta-cel Therapy for Relapsed or Refractory Myeloma. N Engl J Med 2025; 392:677-685. [PMID: 39938094 DOI: 10.1056/nejmoa2309728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/14/2025]
Abstract
We describe two patients in whom malignant monoclonal T-cell lymphoproliferation developed after administration of chimeric antigen receptor (CAR) T-cell therapy with ciltacabtagene autoleucel (cilta-cel) in the phase 3 CARTITUDE-4 trial. Monoclonal T cells from both patients had detectable CAR transgene expression and integration. The clinicogenomic features of these CAR transgenic T-cell lymphoproliferative neoplasms suggest that multiple potential intrinsic or extrinsic factors (or both) contributed to their pathogenesis, such as transduction of preexisting TET2-mutated T cells, followed by acquisition of further oncogenic genomic variants. Other potential contributors include germline genomic variation, viral infections, and previous treatment for myeloma. In the absence of direct evidence, the contribution of insertional mutagenesis to the development of T-cell lymphoma is currently unclear. (Funded by Johnson & Johnson and Legend Biotech USA; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.).
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Affiliation(s)
- Simon J Harrison
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Royal Melbourne Hospital, Melbourne, VIC, Australia
- Translation Laboratory, Centre of Excellence in Cellular Immunotherapy, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
| | - Cyrille Touzeau
- Service d'Hématologie, Centre Hospitalier Universitaire (CHU) Hôtel Dieu, Nantes, France
- Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers, INSERM, Centre National de la Recherche Scientifique, Université d'Angers, Université de Nantes, Nantes, France
- Site de Recherche Intégrée sur le Cancer, Imaging and Longitudinal Investigations to Ameliorate Decision-making (ILIAD), French National Cancer Institute-French Ministry of Health-INSERM 12558, Nantes, France
| | - Nicolas Kint
- Dienst Klinische Hematologie, Universitair Ziekenhuis Gent, Ghent, Belgium
| | | | - Tamia Nguyen
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
| | | | - Marzia Rahman
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Royal Melbourne Hospital, Melbourne, VIC, Australia
| | - Yannick Le Bris
- Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers, INSERM, Centre National de la Recherche Scientifique, Université d'Angers, Université de Nantes, Nantes, France
- Site de Recherche Intégrée sur le Cancer, Imaging and Longitudinal Investigations to Ameliorate Decision-making (ILIAD), French National Cancer Institute-French Ministry of Health-INSERM 12558, Nantes, France
- Laboratoire d'Hématologie, CHU Hôtel Dieu, Nantes, France
| | - Jeremy Er
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Royal Melbourne Hospital, Melbourne, VIC, Australia
- Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
| | | | - Nicole M Haynes
- Translation Laboratory, Centre of Excellence in Cellular Immunotherapy, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
| | - Jessica Li
- Translation Laboratory, Centre of Excellence in Cellular Immunotherapy, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Rebecca C Abbott
- Translation Laboratory, Centre of Excellence in Cellular Immunotherapy, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
| | - Caroline Bodet-Milin
- Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers, INSERM, Centre National de la Recherche Scientifique, Université d'Angers, Université de Nantes, Nantes, France
- Site de Recherche Intégrée sur le Cancer, Imaging and Longitudinal Investigations to Ameliorate Decision-making (ILIAD), French National Cancer Institute-French Ministry of Health-INSERM 12558, Nantes, France
- Service de Médecine Nucléaire, CHU, Nantes, France
| | - Anne Moreau
- Laboratoire d'Anatomo-Pathologie, CHU, Nantes, France
| | - Eric Letouzé
- Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers, INSERM, Centre National de la Recherche Scientifique, Université d'Angers, Université de Nantes, Nantes, France
- Site de Recherche Intégrée sur le Cancer, Imaging and Longitudinal Investigations to Ameliorate Decision-making (ILIAD), French National Cancer Institute-French Ministry of Health-INSERM 12558, Nantes, France
| | | | | | | | | | | | | | | | - Hao Zhao
- Johnson & Johnson, Spring House, PA
| | | | | | | | - Erin Lee
- Johnson & Johnson, Titusville, NJ
| | | | | | | | | | | | | | - Thomas Gastinne
- Service d'Hématologie, Centre Hospitalier Universitaire (CHU) Hôtel Dieu, Nantes, France
| | - Hannah Kelly
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Royal Melbourne Hospital, Melbourne, VIC, Australia
| | - Ing Soo Tiong
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Royal Melbourne Hospital, Melbourne, VIC, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
| | - Marion Eveillard
- Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers, INSERM, Centre National de la Recherche Scientifique, Université d'Angers, Université de Nantes, Nantes, France
- Site de Recherche Intégrée sur le Cancer, Imaging and Longitudinal Investigations to Ameliorate Decision-making (ILIAD), French National Cancer Institute-French Ministry of Health-INSERM 12558, Nantes, France
- Laboratoire d'Hématologie, CHU Hôtel Dieu, Nantes, France
| | - Patrice Chevallier
- Service d'Hématologie, Centre Hospitalier Universitaire (CHU) Hôtel Dieu, Nantes, France
- Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers, INSERM, Centre National de la Recherche Scientifique, Université d'Angers, Université de Nantes, Nantes, France
| | - Stephen Lade
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Royal Melbourne Hospital, Melbourne, VIC, Australia
| | - Philippe Moreau
- Service d'Hématologie, Centre Hospitalier Universitaire (CHU) Hôtel Dieu, Nantes, France
- Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers, INSERM, Centre National de la Recherche Scientifique, Université d'Angers, Université de Nantes, Nantes, France
- Site de Recherche Intégrée sur le Cancer, Imaging and Longitudinal Investigations to Ameliorate Decision-making (ILIAD), French National Cancer Institute-French Ministry of Health-INSERM 12558, Nantes, France
| | - Sean Grimmond
- Collaborative Center for Genomic Cancer Medicine, University of Melbourne, Melbourne, VIC, Australia
| | - Jane Oliaro
- Translation Laboratory, Centre of Excellence in Cellular Immunotherapy, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
| | - Benoit Tessoulin
- Service d'Hématologie, Centre Hospitalier Universitaire (CHU) Hôtel Dieu, Nantes, France
- Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers, INSERM, Centre National de la Recherche Scientifique, Université d'Angers, Université de Nantes, Nantes, France
| | - Piers Blombery
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Royal Melbourne Hospital, Melbourne, VIC, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
- Collaborative Center for Genomic Cancer Medicine, University of Melbourne, Melbourne, VIC, Australia
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4
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Soma L, Crisan L, Reid J, Lee W, Song J, Afkhami M, Shouse G, Fei F, Danilova O, Pillai R, Zain J, Querfeld C. Epstein-Barr virus-positive, primary cutaneous marginal zone lymphoma, with transformation: Case report and review of the literature. Am J Clin Pathol 2025; 163:298-312. [PMID: 39290045 DOI: 10.1093/ajcp/aqae124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 08/22/2024] [Indexed: 09/19/2024] Open
Abstract
INTRODUCTION Epstein-Barr Virus (EBV) positive primary cutaneous marginal zone lymphoma (PCMZL) is uncommon and subsequent transformation is rare. METHODS We report a patient with EBV positive PCMZL with subsequent transformation to plasmablastic lymphoma and review the literature for transformed PCMZL to assess clinical and pathologic characteristics. In the case we describe, the patient presented with multifocal PCMZL, developed large B cell transformation with plasmacytic differentiation, followed by plasmablastic transformation (PBL), and ultimately died of disease progression despite multiple lines of therapy. Past history was significant for psoriatic arthritis (multiple prior lines of immunomodulatory therapy). The lymphomas and non-involved bone marrow share the same somatic DNMT3A and TET2 mutations, suggesting clonal relatedness and an association with clonal hematopoiesis (CH). RESULTS Eighteen cases comprised the cohort (seventeen cases from the literature and the case reported herein). Nearly half of the eighteen cases of PCMZL with transformation died of progressive disease (44%). Transformed cases were more commonly seen in patients with >2 sites at initial diagnosis. EBV was assessed in 5 patients, 3 were positive (all died of disease). Two patients with NGS studies demonstrated TET2 and DNMT3A mutations. CONCLUSIONS Transformation of EBV positive PCMZL appears to be a poor prognostic indicator, with our reported case being the first well defined case transformed to PBL, suspected to arise from myeloid-CH.
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MESH Headings
- Humans
- Lymphoma, B-Cell, Marginal Zone/pathology
- Lymphoma, B-Cell, Marginal Zone/virology
- Lymphoma, B-Cell, Marginal Zone/genetics
- Skin Neoplasms/pathology
- Skin Neoplasms/virology
- Skin Neoplasms/genetics
- Male
- Epstein-Barr Virus Infections/complications
- Epstein-Barr Virus Infections/pathology
- Middle Aged
- Herpesvirus 4, Human/genetics
- Herpesvirus 4, Human/isolation & purification
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/pathology
- Fatal Outcome
- Aged
- Mutation
- Female
- DNA Methyltransferase 3A
- Plasmablastic Lymphoma/pathology
- Plasmablastic Lymphoma/virology
- Plasmablastic Lymphoma/diagnosis
- Plasmablastic Lymphoma/genetics
- DNA-Binding Proteins
- Dioxygenases
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Affiliation(s)
- Lori Soma
- Department of Pathology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, US
| | - Liliana Crisan
- Department of Pathology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, US
| | - Jack Reid
- Department of Pathology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, US
| | - Winston Lee
- Department of Pathology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, US
| | - Joo Song
- Department of Pathology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, US
| | - Michelle Afkhami
- Department of Pathology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, US
| | - Geoffrey Shouse
- Department of Hematology and Hematopoietic Cell Transplant, Division of Lymphoma, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, US
| | - Fei Fei
- Department of Pathology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, US
| | - Olga Danilova
- Department of Pathology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, US
| | - Raju Pillai
- Department of Pathology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, US
| | - Jasmin Zain
- Department of Hematology and Hematopoietic Cell Transplant, Division of Lymphoma, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, US
| | - Christiane Querfeld
- Department of Pathology, Division of Dermatology, Department of Hematology and Hematopoietic Cell Transplantation, and Beckman Research Institute, City of Hope Medical Center, Duarte, CA, US
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5
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Poon G, Vedi A, Sanders M, Laurenti E, Valk P, Blundell JR. Single-cell DNA sequencing reveals pervasive positive selection throughout preleukemic evolution. CELL GENOMICS 2025; 5:100744. [PMID: 39842433 DOI: 10.1016/j.xgen.2024.100744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 08/03/2024] [Accepted: 12/26/2024] [Indexed: 01/24/2025]
Abstract
The representation of driver mutations in preleukemic hematopoietic stem cells (pHSCs) provides a window into the somatic evolution that precedes acute myeloid leukemia (AML). Here, we isolate pHSCs from the bone marrow of 16 patients diagnosed with AML and perform single-cell DNA sequencing on thousands of cells to reconstruct phylogenetic trees of the major driver clones in each patient. We develop a computational framework that can infer levels of positive selection operating during preleukemic evolution from the statistical properties of these phylogenetic trees. Combining these data with 67 previously published phylogenetic trees, we find that the highly variable structures of preleukemic trees emerge naturally from a simple model of somatic evolution with pervasive positive selection typically in the range of 9%-24% per year. At these levels of positive selection, we show that the identification of early multiple-mutant clones could be used to identify individuals at risk of future AML.
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Affiliation(s)
- Gladys Poon
- Early Cancer Institute, University of Cambridge, Cambridge, UK.
| | - Aditi Vedi
- Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
| | - Mathijs Sanders
- Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Elisa Laurenti
- Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Peter Valk
- Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
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6
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Iyama S, Chi S, Idogawa M, Ikezoe T, Fukushima K, Utsu Y, Kanda J, Yoshimoto G, Kobayashi T, Hosono N, Yamauchi T, Kondo T, Nakamura Y, Kojima K, Yoshida C, Gotoh A, Yamamoto K, Kuroda J, Ishitsuka K, Sakaida E, Horiguchi H, Takada K, Ohnishi H, Kobune M, Minami Y. Prognostic impact of TET2 mutations in patients with acute myeloid leukemia: HM-SCREEN-Japan 01 and 02 study. Ann Hematol 2025:10.1007/s00277-025-06227-y. [PMID: 39921715 DOI: 10.1007/s00277-025-06227-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 01/24/2025] [Indexed: 02/10/2025]
Abstract
Ten-eleven translocation-2 (TET2) gene mutations are observed in 12-20% of adult patients with acute myeloid leukemia (AML). The prognostic impact of TET2 mutations in patients with AML and myelodysplastic syndromes has been reported in several studies; however, their results remain controversial. Therefore, we aimed to analyze the prevalence and significance of TET2 mutations in patients with AML. Data were obtained from 331 patients with AML according to the Hematologic Malignancies-SCREEN-Japan 01 and 02 studies, which were prospective multicenter genomic profiling analyses. We found a distinct type of TET2 mutations, with a particularly detrimental prognosis in the patients. Thirty-five patients with TET2 'significant' mutations were identified (26 with frameshift mutations and nine with nonsense mutations). The proportion of patients with TET2 mutations was 31.7% (10.6% and 21.1% in the TET2 significant and non-significant mutation groups). The TET2 significant mutation group had a shorter OS than the TET2 non-significant mutation or wild-type TET2 group (median: 15.9 vs. 35.0 vs. 25.9 months). Regarding the response to chemotherapy according to TET2 status, the complete response (CR) or CR with incomplete count recovery rate was 37.1% in the TET2 significant mutation group and 46.6% in the non-significant mutation or wild-type group. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) improved patient prognosis in the TET2 non-significant mutation or wild-type TET2 group; however, allo-HSCT did not affect prognosis in the TET2 significant mutation group. This study indicates that certain TET2 mutations in patients with AML may have detrimental effects.
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Affiliation(s)
- Satoshi Iyama
- Department of Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo- ku, Sapporo, 060-8543, Hokkaido, Japan.
| | - SungGi Chi
- Department of Hematology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Masashi Idogawa
- Department of Medical Genome Sciences, Cancer Research Institute, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takayuki Ikezoe
- Department of Hematology, Fukushima Medical University, Fukushima, Japan
| | - Kentaro Fukushima
- Department of Hematology and Oncology, Osaka University, Suita, Japan
| | - Yoshikazu Utsu
- Department of Hematology and Oncology, Japanese Red Cross Narita Hospital, Narita, Japan
| | - Junya Kanda
- Department of Hematology, Kyoto University, Kyoto, Japan
| | - Goichi Yoshimoto
- Department of Hematology, Saga Prefectural Kouseikan Hospital, Saga, Japan
| | - Takahiro Kobayashi
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
| | - Naoko Hosono
- Department of Hematology and Oncology, University of Fukui Hospital, Fukui, Japan
| | - Takahiro Yamauchi
- Department of Hematology and Oncology, University of Fukui Hospital, Fukui, Japan
| | - Takeshi Kondo
- Blood Disorders Center, Aiiku Hospital, Sapporo, Japan
| | - Yukinori Nakamura
- Third Department of Internal Medicine, Yamaguchi University Hospital, Ube, Japan
| | - Kensuke Kojima
- Department of Hematology, Kochi Medical School Hospital, Nankoku, Japan
| | - Chikashi Yoshida
- Department of Hematology, NHO Mito Medical Center, Ibaraki, Japan
| | - Akihiko Gotoh
- Department of Hematology, Tokyo Medical University Hospital, Tokyo, Japan
| | - Kazuhito Yamamoto
- Department Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan
| | - Junya Kuroda
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kenji Ishitsuka
- Department of Hematology and Rheumatology, Kagoshima University, Kagoshima, Japan
| | - Emiko Sakaida
- Department of Hematology, Chiba University Hospital, Chiba, Japan
| | - Hiroto Horiguchi
- Department of Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo- ku, Sapporo, 060-8543, Hokkaido, Japan
| | - Kohichi Takada
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hirofumi Ohnishi
- Department of Public Health, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masayoshi Kobune
- Department of Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo- ku, Sapporo, 060-8543, Hokkaido, Japan
| | - Yosuke Minami
- Department of Hematology, National Cancer Center Hospital East, Kashiwa, Japan
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7
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Pradhan K, Neupane B, Niehues P, Kirschner M, Beier F, Kuo CC, Hilbold EA, Bär C, Thoma OM, Waldner M, Vieri M, Brümmendorf TH, Tharmapalan V, Wagner W, Kleines M, Emrani M, Zink MD, Napp A, Marx N, Gramlich M. Telomere Length Is Associated With Adverse Atrial Remodeling in Patients With Atrial Fibrillation. J Am Heart Assoc 2025; 14:e037512. [PMID: 39895528 DOI: 10.1161/jaha.124.037512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 12/20/2024] [Indexed: 02/04/2025]
Abstract
BACKGROUND Atrial fibrillation (AF) is the most common cardiac arrhythmia with a massive burden on global health. The prevalence of AF increases dramatically with age and can be up to 18% in patients older than 80 years. Telomeres, which are short, repeated DNA sequences at the end of chromosomes, are known to act as a biological aging marker. In this study, we investigated the relation of telomere shortening and AF in the context of atrial remodeling. Furthermore, we assessed changes in the gene expression profiles of patients with AF according to telomere length (TL) and left atrial fibrosis. METHODS We included 72 patients undergoing catheter ablation for AF. Bipolar voltage maps were obtained to determine left atrial low voltage areas as a surrogate for atrial fibrosis. TL was quantified and correlated to low voltage areas. 3' mRNA sequencing was performed for gene expression profiling. Clonal hematopoiesis of indeterminate potential was assessed by next generation sequencing. Telomerase reverse transcriptase knockout (Tert-/-) and telomerase RNA component knockout (Terc-/-) mice were used to investigate the mechanistic impact of telomere shortening on atrial remodeling. RESULTS Patients with advanced left atrial fibrosis had shorter telomeres compared with patients with healthy left atria. Furthermore, there was a strong correlation between the extent of left atrial low voltage areas, TL, and outcome after catheter ablation of AF. 24 months after ablation, only 26.5% of patients with advanced fibrosis and short TL were in sinus rhythm compared with 62.5% of patients with no/low fibrosis and long TL. Gene expression profiles and clonal hematopoiesis of indeterminate potential frequency differed in patients with AF with short and long telomeres. Finally, atrial tissue of mouse models with shortened telomeres showed marked left atrial fibrosis and over-expression of fibrosis-related genes. CONCLUSIONS Telomere shortening is correlated with left atrial remodeling. Shorter telomeres are associated with a series of molecular events which could eventually lead to cardiac fibrosis and perpetuate AF.
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Affiliation(s)
- Kabita Pradhan
- Department of Cardiology University Hospital RWTH Aachen Aachen Germany
| | - Balram Neupane
- Department of Cardiology University Hospital RWTH Aachen Aachen Germany
| | - Paul Niehues
- Department of Cardiology University Hospital RWTH Aachen Aachen Germany
| | - Martin Kirschner
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty University Hospital RWTH Aachen Aachen Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD) Cologne Germany
| | - Fabian Beier
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty University Hospital RWTH Aachen Aachen Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD) Cologne Germany
| | - Chao-Chung Kuo
- Genomics Facility, Interdisciplinary Center for Clinical Research (IZKF) University Hospital RWTH Aachen Aachen Germany
| | - Erika Anneliese Hilbold
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS) Hannover Medical School Hannover Germany
| | - Christian Bär
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS) Hannover Medical School Hannover Germany
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) Hannover Germany
| | - Oana-Maria Thoma
- Department of Medicine 1 Friedrich-Alexander-Universität Erlangen-Nürnberg Erlangen Germany
- German Center for Immunotherapy, Deutsches Zentrum Immuntherapie (DZI) University Hospital Erlangen Erlangen Germany
| | - Maximilian Waldner
- Department of Medicine 1 Friedrich-Alexander-Universität Erlangen-Nürnberg Erlangen Germany
- German Center for Immunotherapy, Deutsches Zentrum Immuntherapie (DZI) University Hospital Erlangen Erlangen Germany
| | - Margherita Vieri
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty University Hospital RWTH Aachen Aachen Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD) Cologne Germany
| | - Tim H Brümmendorf
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty University Hospital RWTH Aachen Aachen Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD) Cologne Germany
| | - Vithurithra Tharmapalan
- Institute for Stem Cell Biology, Helmholtz Institute for Biomedical Engineering University Hospital RWTH Aachen Aachen Germany
| | - Wolfgang Wagner
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD) Cologne Germany
- Institute for Stem Cell Biology, Helmholtz Institute for Biomedical Engineering University Hospital RWTH Aachen Aachen Germany
| | - Michael Kleines
- Division of Virology, Center of Laboratory Diagnostics University Hospital RWTH Aachen Aachen Germany
| | - Mahdi Emrani
- Department of Cardiology University Hospital RWTH Aachen Aachen Germany
| | | | - Andreas Napp
- Department of Cardiology University Hospital RWTH Aachen Aachen Germany
| | - Nikolaus Marx
- Department of Cardiology University Hospital RWTH Aachen Aachen Germany
| | - Michael Gramlich
- Department of Cardiology University Hospital RWTH Aachen Aachen Germany
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Arber DA, Orazi A. The Diagnostic Spectrum of Myelodysplastic Syndromes and Acute Myeloid Leukemia. Adv Anat Pathol 2025:00125480-990000000-00137. [PMID: 39895485 DOI: 10.1097/pap.0000000000000485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
The International Consensus Classification (ICC) of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) expands on the work of prior classifications to refine the diagnostic criteria for MDS and AML and to identify specific genetic disease subtypes. This review summarizes the approach to the diagnosis of MDS and AML from the ICC perspective. For MDS, the significance of detecting mutations in SF3B1, usually associated with ring sideroblasts, as well as the poor prognosis of mutations of TP53 are now included. For AML, new genetic categories are included, and the classification now incorporates additional clinically significant gene mutations by recognizing AML with TP53 mutation and AML with mutations in genes associated with prior therapy or MDS. Finally, the new category of MDS/AML is introduced for adult patients without recurrent de novo genetic abnormalities with 10% to 19% peripheral blood or bone marrow blasts that allow for more treatment flexibility based on clinical findings. While the increase in genetic categories and changes in blast cell requirements can be confusing, a stepwise approach is provided to allow easy use of the classification.
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Affiliation(s)
- Daniel A Arber
- Department of Pathology, University of Chicago, Chicago, IL
| | - Attilio Orazi
- Department of Pathology, Texas Tech University Health Sciences Center El Paso, El Paso, TX
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9
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White MG, Zeineddine MA, Fallon EA, Zeineddine FA, Dansby J, Chowdhury S, Hornstein N, Yousef A, Yousef M, Bhutiani N, Gu Y, Kee B, Dasari A, Overman MJ, Raghav K, Kopetz S, Uppal A, Taggart M, Newhook T, Fournier K, Helmink B, Drusbosky LM, Shen JP. The Landscape of ctDNA in Appendiceal Adenocarcinoma. Clin Cancer Res 2025; 31:551-560. [PMID: 39679931 PMCID: PMC11790361 DOI: 10.1158/1078-0432.ccr-24-2474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 09/23/2024] [Accepted: 12/06/2024] [Indexed: 12/17/2024]
Abstract
PURPOSE Appendiceal adenocarcinoma is a rare malignancy with distinct histopathologic subtypes and a natural history with metastasis primarily limited to the peritoneum. Little is known about the molecular pathogenesis of appendiceal adenocarcinoma relative to common tumors. EXPERIMENTAL DESIGN We analyzed molecular data for patients within the Guardant Health database with appendix cancer (n = 718). We then identified patients with appendiceal adenocarcinoma at our institution (from October 2004-September 2022) for whom ctDNA mutation profiling (liquid biopsy) was performed (n = 168) and extracted clinicopathologic and outcomes data. Of these 168 patients, 57 also had tissue-based tumor mutational profiling, allowing for evaluation of concordance between liquid and tissue assays. RESULTS The mutational landscape of ctDNA in appendiceal adenocarcinoma is distinct from tissue-based sequencing, with TP53 being the most frequently mutated (46%). Relative to other tumors, appendiceal adenocarcinoma seems less likely to shed ctDNA, with only 38% of patients with metastatic appendiceal adenocarcinoma having detectable ctDNA (OR = 0.26; P < 0.0001 relative to colorectal cancer). When detectable, the median variant allele frequency was significantly lower in appendiceal adenocarcinoma (0.4% vs. 1.3% for colorectal cancer; P ≤ 0.001). High-grade, signet ring, or colonic-type histology, metastatic spread beyond the peritoneum, and TP53 mutation were associated with detectable ctDNA. With respect to clinical translation, patients with detectable ctDNA had worse overall survival (HR = 2.32; P = 0.048). In the Guardant Health cohort, actionable mutations were found in 93 patients (13.0%). CONCLUSIONS Although metastatic appendiceal adenocarcinoma tumors are less likely to shed tumor DNA into the blood relative to colorectal cancer, ctDNA profiling in appendiceal adenocarcinoma has clinical utility.
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Affiliation(s)
- Michael G. White
- Department of Colon & Rectal Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Mohammad A. Zeineddine
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Eleanor A. Fallon
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Fadl A. Zeineddine
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Julia Dansby
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Saikat Chowdhury
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Nicholas Hornstein
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Abdelrahman Yousef
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Mahmoud Yousef
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Neal Bhutiani
- Department of Colon & Rectal Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Yue Gu
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Bryan Kee
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Arvind Dasari
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Michael J. Overman
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Kanwal Raghav
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Abhineet Uppal
- Department of Colon & Rectal Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Melissa Taggart
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Timothy Newhook
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Keith Fournier
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Beth Helmink
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | - John Paul Shen
- Department of Colon & Rectal Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX
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Sánchez-Lanzas R, Barclay J, Hardas A, Kalampalika F, Jiménez-Pompa A, Gallipoli P, Ganuza M. A CADASIL NOTCH3 mutation leads to clonal hematopoiesis and expansion of Dnmt3a-R878H hematopoietic clones. Leukemia 2025; 39:460-472. [PMID: 39537978 PMCID: PMC11794143 DOI: 10.1038/s41375-024-02464-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 10/30/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
Clonal hematopoiesis (CH) is nearly universal in the elderly. The molecular and cellular mechanisms driving CH and the clinical consequences of carrying clonally derived mutant mature blood cells are poorly understood. We recently identified a C223Y mutation in the extracellular domain (ECD) of NOTCH3 as a putative CH driver in mice. Provocatively, germline NOTCH3 ECD mutations perturbing cysteine numbers cause Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a type of vascular dementia, suggesting an unexpected link between CADASIL and CH. Here, we formally demonstrated that mouse hematopoietic stem and progenitor cells (HSPCs) expressing CADASIL-related NOTCH3C455R exhibit a proliferative advantage resulting in robust cellular expansion in vivo and in vitro. Co-expression of NOTCH3C455R and Dnmt3aR878H, homologous to a frequent human CH mutation, increased the fitness of NOTCH3C455R HSPCs, demonstrating their functional cooperation. Surprisingly, the presence of NOTCH3C455R hematopoietic cells supported the expansion of Dnmt3aR878H HSPCs in a non-cell autonomous fashion in vivo, strongly suggesting that CADASIL patients and asymptomatic carriers can be highly predisposed to DNMT3AR882H-driven CH. Considering that CADASIL-related NOTCH3 mutations are more frequent in the general population than anticipated (~1 carrier in 400 people), the effect of these NOTCH3 mutations on CH development should be considered.
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Affiliation(s)
- Raúl Sánchez-Lanzas
- Centre for Hemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Justin Barclay
- Centre for Hemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Alexandros Hardas
- Royal Veterinary College, Hertfordshire, UK
- Francis Crick Institute, London, UK
| | - Foteini Kalampalika
- Centre for Hemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Amanda Jiménez-Pompa
- Centre for Hemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Paolo Gallipoli
- Centre for Hemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Miguel Ganuza
- Centre for Hemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
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11
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Mittelman M. Introduction to the Review Series on Myelodysplasia. Haematologica 2025; 110:281-282. [PMID: 39895333 PMCID: PMC11788610 DOI: 10.3324/haematol.2023.284948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Accepted: 10/01/2024] [Indexed: 02/04/2025] Open
Affiliation(s)
- Moshe Mittelman
- Tel-Aviv Sourasky Medical Center and Tel-Aviv University Medical School, Tel-Aviv, Israel
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12
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Oster HS, Van de Loosdrecht AA, Mittelman M. Diagnosis of myelodysplastic syndromes: the classic and the novel. Haematologica 2025; 110:300-311. [PMID: 39445407 PMCID: PMC11788627 DOI: 10.3324/haematol.2023.284937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Indexed: 10/25/2024] Open
Abstract
The myelodysplastic syndromes (MDS) are a heterogenous group of clonal bone marrow (BM) stem cell myeloid neoplasms, characterized by BM dysplasia, macrocytic anemia or cytopenia with a tendency for leukemic transformation. The suspicion of MDS is raised by a typical but not specific clinical picture and routine laboratory findings, but the gold standard for the diagnosis of MDS is still BM examination with the presence of uni-or multi-lineage dysplasia and blast percentage, together with exclusion of other reasons. Cytogenetics is also a part of the diagnostic process. Flow cytometry and genetics are helpful but are not always mandatory for the diagnosis of MDS. This review summarizes the current steps in the diagnostic approach for a patient suspected of having MDS. We also describe new concepts that use non-invasive diagnostic technologies, especially digital methods as well as peripheral blood genetics. The hope is that one day these will mature, be introduced into clinical practice, and perhaps in many cases even replace the invasive BM biopsy.
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Affiliation(s)
- Howard S Oster
- Department of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv University School of Medicine
| | - Arjan A Van de Loosdrecht
- Department of Hematology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, Amsterdam
| | - Moshe Mittelman
- Department of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv University School of Medicine.
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13
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Raddatz MA, Pershad Y, Parker AC, Bick AG. Clonal Hematopoiesis of Indeterminate Potential and Cardiovascular Health. Cardiol Clin 2025; 43:13-23. [PMID: 39551555 DOI: 10.1016/j.ccl.2024.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related phenomenon in which somatic mutations lead to clonal expansion of hematopoietic stem cells without the development of hematologic abnormalities. A growing body of literature demonstrates an association between CHIP and cardiovascular disease. This pathophysiology demonstrates a novel connection between global inflammation and cardiovascular morbidity. While there is limited consensus addressing the cardiovascular care of these patients, risk factor optimization and disease surveillance are advisable. Investigation into possible therapies is ongoing and provides promise for the treatment of inflammation contributing to cardiovascular disease in patients with and without CHIP.
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Affiliation(s)
- Michael A Raddatz
- Division of Cardiology, Department of Medicine, University of California, Los Angeles, 650 Charles E. Young Dr. South, A2-237 CHS, Los Angeles, CA 90095, USA
| | - Yash Pershad
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University School of Medicine, 550 Robinson Research Building, Nashville, TN 37232, USA
| | - Alyssa C Parker
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University School of Medicine, 550 Robinson Research Building, Nashville, TN 37232, USA
| | - Alexander G Bick
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University School of Medicine, 550 Robinson Research Building, Nashville, TN 37232, USA.
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14
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Xi Z, Feng H, Chen K, Guo X, Zhu D, Zheng J, Li Y. Clonal hematopoiesis of indeterminate potential is a risk factor of gastric cancer: A Prospective Cohort in UK Biobank study. Transl Oncol 2025; 52:102242. [PMID: 39675251 PMCID: PMC11713744 DOI: 10.1016/j.tranon.2024.102242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 11/18/2024] [Accepted: 12/07/2024] [Indexed: 12/17/2024] Open
Abstract
IMPORTANCE Gastric cancer is often diagnosed at an advanced stage and at order age, identification of high-risk population is needed for detection of early-stage gastric cancer. OBJECTIVE To examine whether clonal hematopoiesis of indeterminate potential (CHIP) is a risk factor of gastric cancer. DESIGN This cohort study used data from the UK Biobank collected from baseline (2006-2010) to the end of follow-up in March 2024. SETTING Data on age, sex, race, alcohol consumption, smoking status and type 2 diabetes were collected at baseline interview. Previous and diagnosed cancer or diseases were collected from self-reported and in-hospital records. PARTICIPANTS Participants with no previous cancer or hematologic disorders were selected. Participants with gastric cancer cases were aged 60.7 (S.D. 6.62), 71.8 % male; controls were aged 56.1 (S.D. 8.11), 47.4 % male. EXPOSURES Whole-exome sequencing was performed on blood samples collected at baseline. A CHIP status was identified based on the mutations on 43 CHIP-related genes. MAIN OUTCOMES AND MEASURES Odds ratio (OR) of CHIP with gastric cancer risk was estimated using multivariable logistic regression models. Participants were grouped based on age and CHIP status to examine if there are differences in the cumulative incidence of gastric cancer. RESULTS Among 402,253 participants, 1,070 incident gastric cancer cases were identified (mean age, 60.7 ± 6.62 years). The prevalence of CHIP at baseline was associated with an increased risk of gastric cancer (cases: 6.54 % vs. controls 5.14 %; OR without adjustment, 1.29; 95 % CI, 1.004 to 1.63). The stratified OR (95 % CI) of individuals aged ≥ 57 was 1.33 (1.02 to 1.72) for overall CHIP, whereas the OR for younger individuals was 0.79 (0.37 to 1.44). CHIP involving DNMT3A (OR, 1.81; 95 % CI, 1.05 to 2.88; P = 0.0193) and ASXL1 (OR, 2.43; 95 % CI, 0.95 to 4.99; P = 0.032) was associated with an increased risk of gastric cancer. These positive associations remained significantly in sensitivity analyses adjusted by known risk factors. Compared to younger individuals and non-CHIP carriers, older participants with CHIP exhibited a significantly higher cumulative incidence of gastric cancer (P < 0.0001). CONCLUSIONS AND RELEVANCE CHIP is associated with gastric cancer in the elderly and contributes to the positive association between DNM3A and ASXL1 mutations and risk of gastric cancer.
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Affiliation(s)
- Zhihui Xi
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, PR China; Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, PR China
| | - Huolun Feng
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, PR China; Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, PR China.
| | - Kunling Chen
- Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, PR China
| | - Xin Guo
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, PR China
| | - Dandan Zhu
- Guangdong Center for Clinical Laboratory, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, PR China
| | - Jiabin Zheng
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, PR China.
| | - Yong Li
- School of Medicine, South China University of Technology, Guangzhou, Guangdong, PR China; Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, PR China.
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15
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Cazzola M, Malcovati L. Genome sequencing in the management of myelodysplastic syndromes and related disorders. Haematologica 2025; 110:312-329. [PMID: 39445412 PMCID: PMC11788631 DOI: 10.3324/haematol.2023.284947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 07/18/2024] [Indexed: 10/25/2024] Open
Abstract
Myeloid neoplasms originate from the clonal proliferation of hematopoietic stem cells, which is driven by the acquisition of somatic genetic mutations. Within these disorders, myelodysplastic syndromes (MDS) are specifically characterized by morphological abnormalities (dysplasia) and impaired maturation of myeloid precursors (ineffective hematopoiesis), resulting in peripheral blood cytopenia. Several studies have advanced the field of MDS, with a few landmark papers leading to a paradigm shift, opening new avenues of research and enabling a molecular revolution. These seminal papers include the first description of the 5q- syndrome, the identification of somatic mutations of TET2 in myeloid neoplasms, the detection of common pathway mutations in the splicing machinery, and the discovery of clonal hematopoiesis. The somatic genomic landscape of MDS is now well defined. Genes that are recurrently mutated include epigenetic regulators, as well as genes of RNA splicing machinery, transcription regulation, DNA repair control, cohesin complex, and signal transduction. Furthermore, several disorders with a germline genetic predisposition to MDS have been identified, collectively accounting for up to 15% of all MDS cases. Genomic profiling can significantly improve the diagnostic approach to MDS, allowing the identification of distinct nosological entities such as SF3B1-mutant or TP53-mutant MDS. The Molecular International Prognostic Scoring System for MDS has already proven to be a valuable tool for individualized risk assessment and treatment decisions. In addition, the recently developed molecular taxonomy of MDS will likely facilitate the implementation of precision medicine approaches for these disorders. This will necessitate the establishment of specialized infrastructures within public health systems, involving close collaboration between healthcare institutions, academia, and the life-sciences industry.
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Affiliation(s)
- Mario Cazzola
- Department of Molecular Medicine, University of Pavia, and Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia.
| | - Luca Malcovati
- Department of Molecular Medicine, University of Pavia, and Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia
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16
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Xu L, Zhang R, Zhang X, Liu B, Huang D, Liu Y, Shang X. Plasma Proteomes and Genome-Wide Association Data for Causal Protein Identification in Stroke. Mol Neurobiol 2025; 62:2450-2458. [PMID: 39115672 PMCID: PMC11772457 DOI: 10.1007/s12035-024-04411-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 07/30/2024] [Indexed: 01/28/2025]
Abstract
Plasma proteins are promising biomarkers and potential drug targets for stroke. This study aimed to explore whether there is a causal relationship between plasma proteins and subtypes of stroke using a Mendelian randomization (MR) approach. A two-sample bidirectional Mendelian randomization approach was employed to investigate the causal link between plasma proteins and stroke. Data on plasma proteins were obtained from three studies, including INTERVAL, and pooled stroke information was sourced from the MEGASTROKE consortium and the UK Biobank dataset, covering four subtypes of stroke. MR analyses were primarily conducted using inverse variance weighting, and sensitivity analyses were also performed. Finally, potential reverse causality was assessed using bidirectional MR. We identified two proteins causally associated with stroke: one as a potential therapeutic target and another as a protective factor. CXCL8 was found to be positively associated with the risk of developing large-artery atherosclerotic (LAA) stroke (OR, 1.005; 95% CI 1.001 to 1.010; p = 0.022), whereas TNFRSF11b was negatively correlated with the risk of developing LAA stroke (OR, 0.937; 95% CI 0.892 to 0.984; p = 0.010), independently of other stroke subtypes. Reverse bivariate analysis did not indicate that ischemic stroke was causally associated with CXCL8 and TNFRSF11b. There is a causal relationship between CXCL8 and TNFRSF11b with LAA stroke, independent of other subtypes. This study offers a new perspective on the genetics of stroke.
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Affiliation(s)
- Lisi Xu
- Department of The Second Cadre Ward, General Hospital of Northern Theater Command, 83 Wen Hua Road, Shenyang, China
- Department of Neurology, The First Affiliated Hospital of China Medical University, Number 155Heping District, Nanjing Street, Shenyang, China
| | - Ruonan Zhang
- Department of The Second Cadre Ward, General Hospital of Northern Theater Command, 83 Wen Hua Road, Shenyang, China
| | - Xiaolin Zhang
- Department of The Second Cadre Ward, General Hospital of Northern Theater Command, 83 Wen Hua Road, Shenyang, China
| | - Bing Liu
- Department of The Second Cadre Ward, General Hospital of Northern Theater Command, 83 Wen Hua Road, Shenyang, China
| | - Daifa Huang
- Department of The Second Cadre Ward, General Hospital of Northern Theater Command, 83 Wen Hua Road, Shenyang, China
| | - Yanxia Liu
- Department of The Second Cadre Ward, General Hospital of Northern Theater Command, 83 Wen Hua Road, Shenyang, China.
| | - Xiuli Shang
- Department of Neurology, The First Affiliated Hospital of China Medical University, Number 155Heping District, Nanjing Street, Shenyang, China.
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Villaume MT, Savona MR. Pathogenesis and inflammaging in myelodysplastic syndrome. Haematologica 2025; 110:283-299. [PMID: 39445405 PMCID: PMC11788632 DOI: 10.3324/haematol.2023.284944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 09/09/2024] [Indexed: 10/25/2024] Open
Abstract
Myelodysplastic syndromes (MDS) are a genetically complex and phenotypically diverse set of clonal hematologic neoplasms that occur with increasing frequency with age. MDS has long been associated with systemic inflammatory conditions and disordered inflammatory signaling is implicated in MDS pathogenesis. A rise in sterile inflammation occurs with ageing and the term "inflammaging" has been coined by to describe this phenomenon. This distinct form of sterile inflammation has an unknown role in in the pathogenesis of myeloid malignancies despite shared correlations with age and ageing-related diseases. More recent is a discovery that many cases of MDS arise from clonal hematopoiesis of indeterminate potential (CHIP), an age associated, asymptomatic pre-disease state. The interrelationship between ageing, inflammation and clonal CHIP is complex and likely bidirectional with causality between inflammaging and CHIP potentially instrumental to understanding MDS pathogenesis. Here we review the concept of inflammaging and MDS pathogenesis and explore their causal relationship by introducing a novel framing mechanism of "pre-clonal inflammaging" and "clonal inflammaging". We aim to harmonize research on ageing, inflammation and MDS pathogenesis by contextualizing the current understanding of inflammaging and the ageing hematopoietic system with what is known about the etiology of MDS via its progression from CHIP.
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Affiliation(s)
- Matthew T Villaume
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Michael R Savona
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232; Vanderbilt-Ingram Cancer Center, Program in Cancer Biology, and Center for Immunobiology Nashville, TN 37232.
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18
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Ivanova VS, Menter T, Cui N, Leary P, Zinner C, Halter JP, Stenner F, Dirnhofer S, Müller A, Tzankov A. Distinct subtypes of post-transplant lymphoproliferative disorders: CHIP-like mutations in early lesions and substantial mutational differences between EBV-positive and EBV-negative diffuse large B-cell lymphomas. Br J Haematol 2025; 206:484-504. [PMID: 39777628 DOI: 10.1111/bjh.19952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 12/04/2024] [Indexed: 01/11/2025]
Abstract
Post-transplant lymphoproliferative disorders (PTLD) and lymphomas in immunocompromised individuals represent significant clinical challenges, with a limited understanding of their pathogenesis. We investigated a PTLD cohort (n = 50) consisting of 'early lesions' (infectious mononucleosis-like PTLD, plasmacytic and follicular hyperplasias), polymorphic PTLD and post-transplant diffuse large B-cell lymphomas (PT-DLBCL). The study also included 15 DLBCL with autoimmune/immunocompromised backgrounds (IS-DLBCL) and 14 DLBCL, not otherwise specified (DLBCL, NOS), as control. To investigate microarchitectural and genetic changes, immunohistochemistry, multiplex immunofluorescence (mIF), fluorescence in situ hybridisation and high-throughput sequencing were performed. Scarcity of viral infections other than Epstein-Barr virus (EBV) was observed. mIF revealed lower Treg infiltration in PT-DLBCL and high CD8+/PD1+ T cells in IS-DLBCL. MYC rearrangements were most common in PT-DLBCL, followed by IS-DLBCL and DLBCL, NOS, all EBV-negative. TP53 mutations were frequent in EBV-negative PT-DLBCL and DLBCL, NOS but absent in 'early lesions'. NOTCH1 mutations were predominant in PT-DLBCL (N1 DLBCL-subgroup). Gene expression profiling showed a significant overlap between 'early lesions' and polymorphic PTLD. The presence of clonal haematopoiesis of indeterminate potential (CHIP)-like mutations and the absence of immune-escape gene mutations in 'early lesions' suggest these disorders may represent clonal expansions driven by exogenic immunosuppression and/or EBV infection 'substituting' for mutations of the latter group of genes.
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Affiliation(s)
- Vanesa-Sindi Ivanova
- Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Thomas Menter
- Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Ningxuan Cui
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Peter Leary
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Carl Zinner
- Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Jörg P Halter
- Haematology, University Hospital Basel, Basel, Switzerland
| | - Frank Stenner
- Oncology, University Hospital Basel, Basel, Switzerland
| | - Stefan Dirnhofer
- Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Anne Müller
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Alexandar Tzankov
- Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
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19
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Kim M. Exploring the Impact of Clonal Hematopoiesis on Heart Failure and Remodeling in Aortic Stenosis. JACC. ADVANCES 2025; 4:101534. [PMID: 39867498 PMCID: PMC11760815 DOI: 10.1016/j.jacadv.2024.101534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Affiliation(s)
- Minkwan Kim
- Division of Cardiology, Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Gyeonggi-do, Republic of Korea
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20
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Bonnefond A, Florez JC, Loos RJF, Froguel P. Dissection of type 2 diabetes: a genetic perspective. Lancet Diabetes Endocrinol 2025; 13:149-164. [PMID: 39818223 DOI: 10.1016/s2213-8587(24)00339-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 09/11/2024] [Accepted: 10/30/2024] [Indexed: 01/18/2025]
Abstract
Diabetes is a leading cause of global mortality and disability, and its economic burden is substantial. This Review focuses on type 2 diabetes, which makes up 90-95% of all diabetes cases. Type 2 diabetes involves a progressive loss of insulin secretion often alongside insulin resistance and metabolic syndrome. Although obesity and a sedentary lifestyle are considerable contributors, research over the last 25 years has shown that type 2 diabetes develops on a predisposing genetic background, with family and twin studies indicating considerable heritability (ie, 31-72%). This Review explores type 2 diabetes from a genetic perspective, highlighting insights into its pathophysiology and the implications for precision medicine. More specifically, the traditional understanding of type 2 diabetes genetics has focused on a dichotomy between monogenic and polygenic forms. However, emerging evidence suggests a continuum that includes monogenic, oligogenic, and polygenic contributions, revealing their complementary roles in type 2 diabetes pathophysiology. Recent genetic studies provide deeper insights into disease mechanisms and pave the way for precision medicine approaches that could transform type 2 diabetes management. Additionally, the effect of environmental factors on type 2 diabetes, particularly from epigenetic modifications, adds another layer of complexity to understanding and addressing this multifaceted disease.
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Affiliation(s)
- Amélie Bonnefond
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Department of Metabolism, Imperial College London, London, UK.
| | - Jose C Florez
- Center for Genomic Medicine and Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Programs in Metabolism and Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Ruth J F Loos
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Philippe Froguel
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Department of Metabolism, Imperial College London, London, UK.
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21
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Kawashima N, Gurnari C, Bravo-Perez C, Kubota Y, Pagliuca S, Guarnera L, Williams ND, Durmaz A, Ahmed A, Dima D, Ullah F, Carraway HE, Singh A, Visconte V, Maciejewski JP. Clonal hematopoiesis in large granular lymphocytic leukemia. Leukemia 2025; 39:451-459. [PMID: 39572711 DOI: 10.1038/s41375-024-02460-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 10/29/2024] [Accepted: 11/01/2024] [Indexed: 02/06/2025]
Abstract
Past studies described occasional patients with myeloid neoplasms (MN) and coexistent large granular lymphocytic leukemia (LGLL) or T-cell clonopathy of unknown significance (TCUS), which may represent expansion of myeloid clonal hematopoiesis (CH) as triggers or targets of clonal cytotoxic T cell reactions. We retrospectively analyzed 349 LGLL/TCUS patients, 672 MN patients, and 1443 CH individuals to establish the incidence, genetic landscape, and clinical phenotypes of CH in LGLL. We identified 8% of cases overlapping with MN, while CH was found in an additional 19% of cases (CH + /LGLL) of which TET2 (23%) and DNMT3A (14%) were the most common. In MN cohort, 3% of cases showed coexistent LGLL. The incidence of CH in LGLL was exceedingly higher than age-matched CH controls (P < 0.0001). By multivariate analysis, the presence of CH in LGLL (P = 0.026) was an independent risk factor for cytopenia in addition to older age (P = 0.003), splenomegaly (P = 0.015) and STAT3/5B mutations (P = 0.001). CH + /LGLL cases also showed a higher progression rate to MN than CH-/LGLL (10% vs. 2% at 5 years; P = 0.02). A close relationship between CH and LGLL suggests that cytopenia in LGLL may be not only related to LGLL but be also secondary to coexisting clonal cytopenia of unclear significance.
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Affiliation(s)
- Naomi Kawashima
- Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Carmelo Gurnari
- Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Carlos Bravo-Perez
- Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Hematology and Medical Oncology, Hospital Universitario Morales Meseguer, University of Murcia, IMIB-Pascual Parrilla, CIBERER - Instituto de Salud Carlos III, Murcia, Spain
| | - Yasuo Kubota
- Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Simona Pagliuca
- Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Clinical Hematology, CHRU de Nancy, Nancy, France
| | - Luca Guarnera
- Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Nakisha D Williams
- Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Arda Durmaz
- Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Arooj Ahmed
- Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Danai Dima
- Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Fauzia Ullah
- Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Hetty E Carraway
- Department of Hematology Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Abhay Singh
- Department of Hematology Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Valeria Visconte
- Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Jaroslaw P Maciejewski
- Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
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22
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Yao CY, Ko TY, Yang LT, Takeuchi M, Yeh CF, Lin MS, Chen YH, Kuo CY, Hsu CL, Chou WC, Kao HL. Clonal Hematopoiesis Is Associated With Adverse Clinical Outcomes and Left Ventricular Remodeling in Aortic Stenosis. JACC. ADVANCES 2025; 4:101532. [PMID: 39886300 PMCID: PMC11780101 DOI: 10.1016/j.jacadv.2024.101532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 11/05/2024] [Accepted: 11/18/2024] [Indexed: 02/01/2025]
Abstract
Background Clonal hematopoiesis of indeterminate potential (CHIP) has been linked to intensified systemic inflammation and represents a novel risk factor for atherosclerotic cardiovascular diseases, including aortic stenosis (AS). Objectives This study aimed to assess the clinical impact of CHIP in a cohort of severe AS patients undergoing transcatheter aortic valve implantation (TAVI). Methods We enrolled 110 severe AS patients in this retrospective study. Targeted next-generation sequencing was employed to detect somatic mutations with a variant allele frequency >2% in 16 genes most frequently associated with CHIP. Correlative analyses on clinical, laboratory, and echocardiographic parameters were also performed. The primary endpoint was post-TAVI heart failure hospitalization. Multivariate Cox regression model was used to account for confounding effects of relevant clinical factors. Results CHIP was detected in 40 (36.4%) patients in our cohort. The most commonly mutated genes were DNMT3A, TET2, and ASXL1. With a median follow-up of 55.2 months, patients carrying CHIP had a significantly higher heart failure hospitalization rate (adjusted HR: 3.060; 95% CI: 1.090-8.589; P = 0.034) than those without CHIP. Additionally, patients harboring CHIP had higher serum ferritin levels, as well as echocardiographic evidence of left ventricular hypertrophy and diastolic dysfunction. Conclusions Our study supports the adverse clinical impact of CHIP in AS patients undergoing TAVI, which could be attributed to systemic inflammation and maladaptive LV remodeling. Prospective trials are anticipated to validate our findings and provide further evidence that CHIP holds the potential of being an actionable therapeutic target in AS.
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Affiliation(s)
- Chi-Yuan Yao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Tsung-Yu Ko
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Li-Tan Yang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Masaaki Takeuchi
- Department of Cardiology, Tobata General Hospital, Kitakyushu, Japan
| | - Chih-Fan Yeh
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Mao-Shin Lin
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Ying-Hsien Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Ching-Ying Kuo
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chia-Lang Hsu
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wen-Chien Chou
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hsien-Li Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
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23
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Patel SA, Weeks LD. Drafting a blueprint for designing successful clinical trials in clonal haematopoiesis. Br J Haematol 2025; 206:800-802. [PMID: 39654077 DOI: 10.1111/bjh.19948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 11/29/2024] [Indexed: 02/16/2025]
Abstract
'As our understanding of the biology of clonal hematopoiesis expands, a pressing need in the field becomes the design and implementation of clinical trials to help mitigate the risk for progression to overt myeloid neoplasm. Effective clinical trial design will be informed by use of personalized genetic risk to determine eligibility, strategic endpoint selection, and identification of suitable interventions with a goldilocks balance of toxicity and reduced risk of progression. We will only reach this milestone through collaboration'. Commentary on: Haque et al. A blueprint for pursuing therapeutic interventions and early phase clinical trials in clonal haematopoiesis. Br J Haematol 2025; 206:416-427.
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Affiliation(s)
- Shyam A Patel
- Department of Medicine-Division of Hematology/Oncology, Center for Clinical and Translational Science, UMass Chan Medical School, Worcester, Massachusetts, USA
| | - Lachelle D Weeks
- Center for Early Detection and Interception of Blood Cancers, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
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24
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Haque T, Shastri A, Desai P, Xie Z, Hammond D, King Z, Kishtagari A, Madanat YF, Abaza Y, Silver AJ, Singh A, Borate UM, Heimlich JB, Slosky DA, Bolton KL, Patnaik MS, Bick AG, Verma AK, Jaiswal S, Steensma DP, Savona MR. A blueprint for pursuing therapeutic interventions and early phase clinical trials in clonal haematopoiesis. Br J Haematol 2025; 206:416-427. [PMID: 39653653 PMCID: PMC11829135 DOI: 10.1111/bjh.19925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 11/17/2024] [Indexed: 02/16/2025]
Abstract
The age-associated mutational state of clonal haematopoiesis (CH) is linked to multiple adverse health outcomes. As higher risk CH can lead to progressive neoplastic or vascular disease, there is interest in developing clinical trials to mitigate risk associated with CH. Given the high prevalence of CH, data from clinical trials could have broad public health implications for screening and therapy. Thoughtful consideration is needed to design trials that are both clinically relevant and avoid overmedicalization. Here, we summarize clinical studies of CH to date and provide suggestions and guidance on how to approach designing CH-focused therapeutic clinical trials. These recommendations are derived from discussions among clinical researchers and scientists emanating from the Inaugural Meeting on Somatic Mutations and Predisease in October 2021.
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Affiliation(s)
- Tamanna Haque
- Department of Medicine, Leukemia ServiceMemorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Aditi Shastri
- Division of Hematologic Malignancies, Department of OncologyMontefiore‐Einstein Comprehensive Cancer CenterBronxNew YorkUSA
| | - Pinkal Desai
- Department of Medicine, Hematology/OncologyCornell UniversityNew YorkNew YorkUSA
| | - Zhuoer Xie
- Malignant Hematology DepartmentMoffit Cancer CenterTampaFloridaUSA
| | | | - Zoe King
- Division of Hematologic Malignancies, Department of OncologyMontefiore‐Einstein Comprehensive Cancer CenterBronxNew YorkUSA
| | - Ashwin Kishtagari
- Department of Medicine, Vanderbilt University School of MedicineVanderbilt‐Ingram Cancer CenterNashvilleTennesseeUSA
| | - Yazan F. Madanat
- Division of Hematology and OncologyUT SouthwesternDallasTexasUSA
| | - Yasmin Abaza
- Department of Medicine, Hematology and OncologyNorthwestern UniversityChicagoIllinoisUSA
| | - Alexander J. Silver
- Department of Medicine, Vanderbilt University School of MedicineVanderbilt‐Ingram Cancer CenterNashvilleTennesseeUSA
| | - Abhay Singh
- Department of Hematology and Medical OncologyCleveland ClinicClevelandOhioUSA
| | - Uma M. Borate
- Division of Hematology, Department of MedicineThe Ohio State University Comprehensive Cancer CenterColumbusOhioUSA
| | - J. Brett Heimlich
- Department of Medicine, Vanderbilt University School of MedicineVanderbilt‐Ingram Cancer CenterNashvilleTennesseeUSA
| | - David A. Slosky
- Division of Cardiology, Department of MedicineUniversity of Wisconsin Medical CenterMadisonWisconsinUSA
| | - Kelly L. Bolton
- Division of Oncology, Department of MedicineWashington University in St. LouisSt. LouisMissouriUSA
| | - Mrinal S. Patnaik
- Division of Hematology, Department of Internal MedicineMayo ClinicRochesterMinnesotaUSA
| | - Alexander G. Bick
- Department of Medicine, Vanderbilt University School of MedicineVanderbilt‐Ingram Cancer CenterNashvilleTennesseeUSA
| | - Amit K. Verma
- Division of Hematologic Malignancies, Department of OncologyMontefiore‐Einstein Comprehensive Cancer CenterBronxNew YorkUSA
| | | | | | - Michael R. Savona
- Department of Medicine, Vanderbilt University School of MedicineVanderbilt‐Ingram Cancer CenterNashvilleTennesseeUSA
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25
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Hajishengallis G, Netea MG, Chavakis T. Trained immunity in chronic inflammatory diseases and cancer. Nat Rev Immunol 2025:10.1038/s41577-025-01132-x. [PMID: 39891000 DOI: 10.1038/s41577-025-01132-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/06/2025] [Indexed: 02/03/2025]
Abstract
A decade after the term 'trained immunity' (TRIM) was coined to reflect the long-lasting hyper-responsiveness of innate immune cells with an epigenetically imprinted 'memory' of earlier stimuli, our understanding has broadened to include the potential implications of TRIM in health and disease. Here, after summarizing the well-documented beneficial effects of TRIM against infections, we discuss emerging evidence that TRIM is also a major underlying mechanism in chronic inflammation-related disorders such as periodontitis, rheumatoid arthritis and cardiovascular disease. Furthermore, mounting evidence indicates that the induction of TRIM by certain agonists confers protective antitumour responses. Although the mechanisms underlying TRIM require further study, the current knowledge enables the experimental development of innovative therapeutic approaches to stimulate or inhibit TRIM in a context-appropriate manner, such as the stimulation of TRIM in cancer or its inhibition in inflammatory disorders.
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Affiliation(s)
- George Hajishengallis
- Department of Basic and Translational Sciences, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
- Department of Immunology and Metabolism, LIMES, University of Bonn, Bonn, Germany.
| | - Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
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26
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Kohutek ZA, Caslin HL, Fehrenbach DJ, Heimlich JB, Brown JD, Madhur MS, Ferrell PB, Doran AC. Bone Marrow Niche in Cardiometabolic Disease: Mechanisms and Therapeutic Potential. Circ Res 2025; 136:325-353. [PMID: 39883790 PMCID: PMC11790260 DOI: 10.1161/circresaha.124.323778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2025]
Abstract
Cardiovascular and cardiometabolic diseases are leading causes of morbidity and mortality worldwide, driven in part by chronic inflammation. Emerging research suggests that the bone marrow microenvironment, or marrow niche, plays a critical role in both immune system regulation and disease progression. The bone marrow niche is essential for maintaining hematopoietic stem cells (HSCs) and orchestrating hematopoiesis. Under normal conditions, this niche ensures a return to immune homeostasis after acute stress. However, in the setting of inflammatory conditions such as those seen in cardiometabolic diseases, it becomes dysregulated, leading to enhanced myelopoiesis and immune activation. This review explores the reciprocal relationship between the bone marrow niche and cardiometabolic diseases, highlighting how alterations in the niche contribute to disease development and progression. The niche regulates HSCs through complex interactions with stromal cells, endothelial cells, and signaling molecules. However, in the setting of chronic diseases such as hypertension, atherosclerosis, and diabetes, inflammatory signals disrupt the balance between HSC self-renewal and differentiation, promoting the excessive production of proinflammatory myeloid cells that exacerbate the disease. Key mechanisms discussed include the effects of hyperlipidemia, hyperglycemia, and sympathetic nervous system activation on HSC proliferation and differentiation. Furthermore, the review emphasizes the role of epigenetic modifications and metabolic reprogramming in creating trained immunity, a phenomenon whereby HSCs acquire long-term proinflammatory characteristics that sustain disease states. Finally, we explore therapeutic strategies aimed at targeting the bone marrow niche to mitigate chronic inflammation and its sequelae. Novel interventions that modulate hematopoiesis and restore niche homeostasis hold promise for the treatment of cardiometabolic diseases. By interrupting the vicious cycle of inflammation and marrow dysregulation, such therapies may offer new avenues for reducing cardiovascular risk and improving patient outcomes.
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Affiliation(s)
- Zachary A Kohutek
- Department of Radiation Oncology (Z.A.K.), Vanderbilt University Medical Center, Nashville, TN
| | - Heather L Caslin
- Department of Health and Human Performance, University of Houston, TX (H.L.C.)
| | - Daniel J Fehrenbach
- Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis (D.J.F., M.S.M.)
| | - J Brett Heimlich
- Division of Cardiovascular Medicine, Department of Medicine (J.B.H., J.D.B., A.C.D.), Vanderbilt University Medical Center, Nashville, TN
| | - Jonathan D Brown
- Division of Cardiovascular Medicine, Department of Medicine (J.B.H., J.D.B., A.C.D.), Vanderbilt University Medical Center, Nashville, TN
| | - Meena S Madhur
- Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis (D.J.F., M.S.M.)
| | - P Brent Ferrell
- Division of Hematology and Oncology, Department of Medicine (P.B.F.), Vanderbilt University Medical Center, Nashville, TN
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University, Nashville, TN (P.B.F., A.C.D.)
| | - Amanda C Doran
- Division of Cardiovascular Medicine, Department of Medicine (J.B.H., J.D.B., A.C.D.), Vanderbilt University Medical Center, Nashville, TN
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University, Nashville, TN (P.B.F., A.C.D.)
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27
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Bentivegna S, Almosailleakh M, Zhao LP, Schuster MB, Benquet S, Balhuizen A, Munch-Petersen HF, Sjö LD, Andersen MH, Dulphy N, Porse B, Grønbæk K. A non-conditioned bone marrow transplantation mouse model to study clonal hematopoiesis and myeloid malignancies. Exp Hematol Oncol 2025; 14:10. [PMID: 39885602 PMCID: PMC11781034 DOI: 10.1186/s40164-025-00598-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 01/15/2025] [Indexed: 02/01/2025] Open
Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) is a condition where blood or bone marrow cells carry mutations associated with hematological malignancies. Individuals with CHIP have an increased risk of developing hematological malignancies, atherosclerotic cardiovascular disease, and all-cause mortality. Bone marrow transplantation (BMT) of cells carrying CHIP mutations into irradiated mice are useful procedures to investigate the dynamics of clonal expansion and potential therapeutic strategies, but myeloablative conditioning can induce confounding effects. We established a non-conditioned BMT model using C57BL/6J-KitW-41J/J (W41) recipient mice to overcome the unwanted effects of irradiation. Conditional Tet2 deletion using tamoxifen was used to obtain Tet2-/- cells from donor mice. Total BM Tet2-/- cells were transplanted into W41 recipients, and longitudinal and terminal analyses at 10 months post-BMT were performed. We showed that W41 mice can be used for BMT procedures without myeloablative pre-conditioning. The transplantation of Tet2-/- BM cells led to a progressive expansion of the donor cells in W41 recipients. By modulating the numbers of Tet2-/- cells transplanted, recipient mice developed features of clonal hematopoiesis or myeloid malignancies. In conclusion, our model is an alternative to conventional irradiation-based transplantation models to study mechanisms underlying malignant hematopoiesis without confounding effects derived from pre-conditioning regimen.
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Affiliation(s)
- Sofia Bentivegna
- Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark
| | - Marwa Almosailleakh
- Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark
| | - Lin-Pierre Zhao
- Hôpital Saint-Louis, Assistance Publique des Hôpitaux de Paris (APHP), Paris, France
- INSERM UMR 1160, Institut de Recherche Saint-Louis, Université Paris Cité, Paris, France
| | - Mikkel Bruhn Schuster
- Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark
- The Finsen Laboratory, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Sébastien Benquet
- Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark
| | - Alexander Balhuizen
- Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark
| | | | - Lene Dissing Sjö
- Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Mads Hald Andersen
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Nicolas Dulphy
- INSERM UMR 1160, Institut de Recherche Saint-Louis, Université Paris Cité, Paris, France
- Laboratoire d'Immunologie et d'Histocompatibilité, Assistance Publique des Hôpitaux de Paris (APHP), Hôpital Saint-Louis, Paris, France
- Institut Carnot OPALE, Institut de Recherche Saint-Louis, Hôpital Saint-Louis, Paris, France
| | - Bo Porse
- Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark
- The Finsen Laboratory, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kirsten Grønbæk
- Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
- Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark.
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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28
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Mohammed Ismail W, Fernandez JA, Binder M, Lasho TL, Kim M, Geyer SM, Mazzone A, Finke CM, Mangaonkar AA, Lee JH, Wang L, Kim KH, Simon VA, Rakhshan Rohakthar F, Munankarmy A, Byeon SK, Schwager SM, Harrington JJ, Snyder MR, Robertson KD, Pandey A, Wieben ED, Chia N, Gaspar-Maia A, Patnaik MM. Single-cell multiomics reveal divergent effects of DNMT3A- and TET2-mutant clonal hematopoiesis in inflammatory response. Blood Adv 2025; 9:402-416. [PMID: 39631069 PMCID: PMC11787483 DOI: 10.1182/bloodadvances.2024014467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 10/28/2024] [Accepted: 11/14/2024] [Indexed: 12/07/2024] Open
Abstract
ABSTRACT DNMT3A and TET2 are epigenetic regulator genes commonly mutated in age-related clonal hematopoiesis (CH). Despite having opposed epigenetic functions, these mutations are associated with increased all-cause mortality and a low risk for progression to hematologic neoplasms. Although individual impacts on the epigenome have been described using different model systems, the phenotypic complexity in humans remains to be elucidated. Here, we make use of a natural inflammatory response occurring during coronavirus disease 2019 (COVID-19), to understand the association of these mutations with inflammatory morbidity (acute respiratory distress syndrome [ARDS]) and mortality. We demonstrate the age-independent, negative impact of DNMT3A mutant (DNMT3Amt) CH on COVID-19-related ARDS and mortality. Using single-cell proteogenomics we show that DNMT3A mutations involve myeloid and lymphoid lineage cells. Using single-cell multiomics sequencing, we identify cell-specific gene expression changes associated with DNMT3A mutations, along with significant epigenomic deregulation affecting enhancer accessibility, resulting in overexpression of interleukin-32 (IL-32), a proinflammatory cytokine that can result in inflammasome activation in monocytes and macrophages. Finally, we show with single-cell resolution that the loss of function of DNMT3A is directly associated with increased chromatin accessibility in mutant cells. Hence, we demonstrate the negative prognostic impact of DNMT3Amt CH on COVID-19-related ARDS and mortality. DNMT3Amt CH in the context of COVID-19, was associated with inflammatory transcriptional priming, resulting in overexpression of IL32. This overexpression was secondary to increased chromatic accessibility, specific to DNMT3Amt CH cells. DNMT3Amt CH can thus serve as a potential biomarker for adverse outcomes in COVID-19.
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Affiliation(s)
- Wazim Mohammed Ismail
- Department of Laboratory Medicine and Pathology, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Jenna A. Fernandez
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Moritz Binder
- Department of Laboratory Medicine and Pathology, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Terra L. Lasho
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Minsuk Kim
- Department of Laboratory Medicine and Pathology, Microbiome Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN
| | - Susan M. Geyer
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN
| | - Amelia Mazzone
- Department of Laboratory Medicine and Pathology, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Christy M. Finke
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | | | - Jeong-Heon Lee
- Department of Laboratory Medicine and Pathology, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN
| | - Liguo Wang
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN
| | - Kwan Hyun Kim
- Department of Laboratory Medicine and Pathology, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN
| | | | | | - Amik Munankarmy
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Seul Kee Byeon
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Susan M. Schwager
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Jonathan J. Harrington
- Department of Laboratory Medicine and Pathology, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN
| | - Melissa R. Snyder
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Keith D. Robertson
- Department of Laboratory Medicine and Pathology, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN
| | - Akhilesh Pandey
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Eric D. Wieben
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN
| | - Nicholas Chia
- Department of Laboratory Medicine and Pathology, Microbiome Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN
| | - Alexandre Gaspar-Maia
- Department of Laboratory Medicine and Pathology, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Mrinal M. Patnaik
- Department of Laboratory Medicine and Pathology, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
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29
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Tan Z, Zhang X, Feng J, Zhao Y, Hu H, Wu D, Yu Q, Zhang Y, Wu L, Hu T, Yan Z, Ye B, Liu W. Hematopoietic stem cell transplantation and immunosuppressive therapy: implications of clonal haematopoiesis. Ann Hematol 2025:10.1007/s00277-024-06152-6. [PMID: 39873798 DOI: 10.1007/s00277-024-06152-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 12/16/2024] [Indexed: 01/30/2025]
Abstract
Aplastic anemia (AA) is a life-threatening bone marrow failure syndrome. The advent of next-generation sequencing (NGS) has shed light on the link between somatic mutations (SM) and the efficacy of immunosuppressive therapy (IST) in AA patients. However, the relationship between SM and hematopoietic stem cell transplantation (HSCT) has not been extensively explored. In this retrospective analysis, we examined 166 AA patients who received HSCT or IST at our institution between May 2019 and December 2023. NGS was conducted on 66 genes within bone marrow cells to investigate the correlation between SM and the prognosis and therapeutic response in AA patients, as well as to assess the impact of mutation types on HSCT outcomes. Clinical data were gathered from 166 AA patients, comprising 84 males and 82 females, with a median age of 32 years (ranging from 9 to 75 years). In our study, a total of 151 somatic mutations were identified across 84 patients (50.6%), with 42 patients (25.3%) presenting a single mutation and 26 patients (15.7%) harboring two mutations. The top five genes with the highest mutation frequency were BCOR/BCORL1 (12.6%), ASXL1 (8.6%), TET2 (6.6%), CEBPA (5.3%), and GATA2 (4.6%). We stratified patients into SM and No-SM groups based on the presence of mutations and further divided them into HSCT and IST groups to assess the influence of mutation types on treatment response and survival within and between these groups. The findings were as follows: 1.Patients in the HSCT group exhibited a higher treatment response (OR 85.9% vs. 68.4%, p < 0.05), although there was no significant difference in survival. 2.Patients with favorable mutations, such as PIGA and BCOR/BCORL1, experienced significantly improved response and survival compared to those with unfavorable mutations like ASXL1, DNMT3A, and TET2 (OR 93.7% vs. 72%, p < 0.05) (3-year OS 93.7% vs. 80%, p > 0.05). 3.The HSCT-Favorable group demonstrated superior response rates (OR 100% vs. 67.7%, p < 0.05) and longer survival (3-year OS 100% vs. 67.7%, p < 0.05) compared to the IST-Favorable group. This study underscores that AA patients carrying favorable mutations, particularly BCOR/BCORL1, tend to have a more robust response and better prognosis than those without mutations or those with unfavorable mutations, such as ASXL1/DNMT3A. These findings are especially pertinent to HSCT, highlighting the importance of NGS prior to initiating treatment.
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Affiliation(s)
- Zhengwei Tan
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xinhe Zhang
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jia Feng
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yuechao Zhao
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Huijin Hu
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Dijiong Wu
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Qinghong Yu
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Yu Zhang
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Liqiang Wu
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Tonglin Hu
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Zhengsong Yan
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Baodong Ye
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Wenbin Liu
- Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China.
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30
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Senguttuvan NB, Subramanian V, Tr M, Sankaranarayanan K, Venkatesan V, Sadagopan T. Clonal hematopoiesis of indeterminate potential and cardiovascular diseases: A review. Indian Heart J 2025:S0019-4832(25)00007-0. [PMID: 39863253 DOI: 10.1016/j.ihj.2025.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 10/08/2024] [Accepted: 01/23/2025] [Indexed: 01/27/2025] Open
Abstract
Cardiovascular disease (CVD) is a major driver of mortality and declining health worldwide. Cardiovascular diseases (CVD) is the most common cause of morbidity and mortality globally. Although dyslipidemia, smoking, diabetes, hypertension and obesity are some well-known causes of CVD, the overlapping genetic pathways between other diseases and those affecting cardiovascular health have been overlooked. In the past decade, mutations in TET2, DNMT3A, ASXL1, and JAK2 are found to cause clonal hematopoiesis of intermediate potential (CHIP), a disease associated with age-related haematological malignancies without the presence of cytopenias or dysplasia. Coronary artery disease, heart failure, aortic stenosis, and arrhythmias have been shown to be associated with the presence of CHIP mutations. Addressing the association between CHIP could significantly reduce residual risk patients with CVD. The link between CHIP and CVD can potentially be addressed through inhibitors of inflammasomes, antagonists in the interleukin pathway, or direct antagonists of CHIP mutations.
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Affiliation(s)
| | - Vinodhini Subramanian
- Department of Human Genetics, Sri Ramachandra Institute of Higher Education & Research (SRIHER), Chennai, India
| | - Muralidharan Tr
- Department of Cardiology, SRM medical college, Chennai, Chennai, India
| | - Kavitha Sankaranarayanan
- Ion Channel Biology Laboratory, AU-KBC Research Centre, MIT Campus of Anna University, Chennai, Tamil Nadu, 600044, India
| | - Vettriselvi Venkatesan
- Department of Human Genetics, Sri Ramachandra Institute of Higher Education & Research (SRIHER), Chennai, India.
| | - Thanikachalam Sadagopan
- Department of Cardiology, Sri Ramachandra Institute of Higher Education & Research (SRIHER), Chennai, India
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31
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Debureaux PE, Poulain S, Harel S, Passet M, Templé M, Friedrich C, Forgeard N, Elessa D, Plas W, Chat L, Lazarian G, Willems L, Royer B, Talbot A, Vaugeois T, Theves F, Terré A, Brignier A, Malphettes M, Krzisch D, Frenzel L, Davi F, Bravetti C, Nguyen-Khac F, Dupuis J, Cuccuini W, Bouscary D, Hermine O, Roos-Weil D, Kosmider O, Clappier E, Espéli M, Balabanian K, Arnulf B. Inflammatory Waldenström macroglobulinemia is associated with clonal hematopoiesis: a multicentric cohort. Blood 2025; 145:450-454. [PMID: 39571148 DOI: 10.1182/blood.2024025738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 10/23/2024] [Indexed: 01/24/2025] Open
Abstract
ABSTRACT Inflammatory form of Waldenström macroglobulinemia (iWM) predicts outcomes after immuno-chemotherapy and Bruton tyrosine kinase inhibitors, but its origin is unknown. Here, we unravel increased clonal hematopoiesis in patients with iWM (61% vs 23% in noninflammatory WM), suggesting a contribution of environmental cells to iWM.
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Affiliation(s)
- Pierre-Edouard Debureaux
- Institut de Recherche Saint-Louis, University Paris Cité, INSERM U1160, Paris, France
- OPALE Carnot Institute, Saint-Louis Hospital, Paris, France
- Department of Immuno-Hematology, Saint-Louis Hospital, Paris, France
| | - Stéphanie Poulain
- Hematology Laboratory, Lille Unité Mixte de Recherche en Santé Hospital, Lille, France
| | - Stéphanie Harel
- Department of Immuno-Hematology, Saint-Louis Hospital, Paris, France
| | - Marie Passet
- Institut de Recherche Saint-Louis, University Paris Cité, INSERM U944/Unité Mixte de Recherche 7212, Paris, France
- Hematology Laboratory, Saint-Louis Hospital, Paris, France
| | - Marie Templé
- Hematobiology Unit, Cochin Hospital, Paris, France
| | | | - Nathalie Forgeard
- Department of Immuno-Hematology, Saint-Louis Hospital, Paris, France
| | - Dikelele Elessa
- Department of Immuno-Hematology, Saint-Louis Hospital, Paris, France
| | - William Plas
- Hematology Laboratory, Saint-Louis Hospital, Paris, France
| | - Laureen Chat
- Hematology Laboratory, Saint-Louis Hospital, Paris, France
| | | | | | - Bruno Royer
- Department of Immuno-Hematology, Saint-Louis Hospital, Paris, France
| | - Alexis Talbot
- Department of Immuno-Hematology, Saint-Louis Hospital, Paris, France
| | - Tristan Vaugeois
- Department of Immuno-Hematology, Saint-Louis Hospital, Paris, France
| | - Floriane Theves
- Department of Immuno-Hematology, Saint-Louis Hospital, Paris, France
| | | | | | | | - Daphné Krzisch
- Immuno-Oncology Unit, Saint-Louis Hospital, Paris, France
- Université Paris Cité, INSERM U1153, Paris, France
| | | | - Frédéric Davi
- Department of Hematology, Pitié-Salpêtrière Hospital, Paris, France
- Sorbonne University, Paris, France
| | | | - Florence Nguyen-Khac
- Laboratory of Cytogenetic, Pitié-Salpêtrière Hospital, Paris, France
- Sorbonne Université, INSERM Unité Mixte de Recherche en Santé 1138, Drug Resistance in Hematological Malignancies Team, Centre de Recherche des Cordeliers, Paris, France
| | - Jehan Dupuis
- Department of Lymphoid Malignancies, Henri Mondor Hospital, Paris, France
| | - Wendy Cuccuini
- Hematology Laboratory, Saint-Louis Hospital, Paris, France
| | | | | | - Damien Roos-Weil
- Department of Hematology, Pitié-Salpêtrière Hospital, Paris, France
- Sorbonne Université, INSERM Unité Mixte de Recherche en Santé 1138, Drug Resistance in Hematological Malignancies Team, Centre de Recherche des Cordeliers, Paris, France
| | | | - Emmanuelle Clappier
- Institut de Recherche Saint-Louis, University Paris Cité, INSERM U944/Unité Mixte de Recherche 7212, Paris, France
- Hematology Laboratory, Saint-Louis Hospital, Paris, France
| | - Marion Espéli
- Institut de Recherche Saint-Louis, University Paris Cité, INSERM U1160, Paris, France
- OPALE Carnot Institute, Saint-Louis Hospital, Paris, France
| | - Karl Balabanian
- Institut de Recherche Saint-Louis, University Paris Cité, INSERM U1160, Paris, France
- OPALE Carnot Institute, Saint-Louis Hospital, Paris, France
| | - Bertrand Arnulf
- Department of Immuno-Hematology, Saint-Louis Hospital, Paris, France
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32
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Qiu JY, Huang SS, Liu C, Ding D, Xu YH, Mao YM, Yuan YD. Genetic evidence for the causal effect of clonal hematopoiesis on pulmonary arterial hypertension. BMC Cardiovasc Disord 2025; 25:38. [PMID: 39849426 PMCID: PMC11755826 DOI: 10.1186/s12872-025-04475-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 01/03/2025] [Indexed: 01/25/2025] Open
Abstract
BACKGROUND Pulmonary arterial hypertension (PAH) is a severe and progressive cardiovascular disease. While potential links between clonal hematopoiesis (CH) and cardiovascular diseases have been identified, the causal relationship between CH and PAH remains unclear. This study aims to investigate the causal effect of CH on the risk of PAH using a two-sample Mendelian randomization (MR) approach. METHODS We utilized genetic variants associated with CH as instrumental variables, identified from two large genome-wide association studies (GWAS) involving 359,088 participants in the discovery cohort and 184,121 participants in the validation cohort, all of European descent. We obtained GWAS summary statistics for PAH. The inverse-variance weighted (IVW) method was employed as the primary analysis, complemented by sensitivity analyses to assess the robustness of our findings. A bidirectional MR analysis was conducted to estimate the causation between CH and PAH. RESULTS Our results indicate a causal effect of CH on the risk of PAH in the discovery cohort, with TET2 showing an IVW odds ratio (OR) of 1.200 (95% CI: 1.001-1.438, P = 0.049). Sensitivity analysis did not reveal significant pleiotropy or heterogeneity. In the validation cohort, we found that TET2 remains a risk factor for PAH (OR = 2.3E + 08, 95% CI 17.007-3.1E + 15, P = 0.022). Additionally, no causal relationship was found between other CH genes, such as DNMT3A and PAH (P > 0.05). The reverse MR analysis provided no evidence of causal effects of PAH on CH. CONCLUSION These findings showed that individuals with CH due to TET2 mutations may have a higher risk of developing PAH, suggesting that the CH patients may be tested for TET2 gene mutations.
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Affiliation(s)
- Jia-Yong Qiu
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, Hebei, China
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, College of Clinical Medicine of Henan, University of Science and Technology, 24 Jinhua Road, Luoyang, China
| | - Shen-Shen Huang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, College of Clinical Medicine of Henan, University of Science and Technology, 24 Jinhua Road, Luoyang, China
| | - Chao Liu
- Department of Cardiology, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Dong Ding
- Institute of Clinical Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, National Infrastructures for Translational Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yan-Hong Xu
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, Hebei, China
| | - Yi-Min Mao
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, College of Clinical Medicine of Henan, University of Science and Technology, 24 Jinhua Road, Luoyang, China.
| | - Ya-Dong Yuan
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, Hebei, China.
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33
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Marshall CH, Antonarakis ES, Patnaik MM. Radiotherapeutics, clonal hematopoiesis, and risk of hematologic malignancies: The good, the bad, the ugly. Blood Rev 2025:101269. [PMID: 39864960 DOI: 10.1016/j.blre.2025.101269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 01/02/2025] [Accepted: 01/21/2025] [Indexed: 01/28/2025]
Abstract
While radiotherapeutics have demonstrated significant clinical benefit across multiple cancer types including thyroid cancer, neuroendocrine tumors, and prostate cancer, hematological toxicities can be frequent and challenging. It remains unknown to what extent the hematologic toxicity is driven by clonal processes that preexist and are selected for by treatment induced selection pressures. In this review, we discuss the background leading to the adoption of radiotherapeutics in the treatment of solid tumor malignancies, the risk of hematologic toxicities and myeloid neoplasms and the evidence pointing to potential precursor lesions that may predispose patients to hematologic toxicities. Additionally, we discuss how prevalent clonal hematopoiesis is among patients with solid tumor malignancies and suggest workflows for patients with cytopenias or clonal hematopoiesis who are receiving or have received radiotherapeutic agents.
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Affiliation(s)
- Catherine H Marshall
- Johns Hopkins School of Medicine, 201 N Broadway, Box 7, Baltimore, MD 21287, United States of America.
| | - Emmanuel S Antonarakis
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, United States of America.
| | - Mrinal M Patnaik
- Mayo Clinic, Division of Hematology, Department of Medicine, 200 1(st) St SW, Rochester, MN 55905, United States of America.
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34
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Zhao X, Li J, Yan S, Tan Y, Chen R, Li N, Zhou J, Liu C, Zhou P, Chen Y, Yan H, Zhao H, Song L. Clonal hematopoiesis of indeterminate potential and type 2 diabetes mellitus among patients with STEMI: from a prospective cohort study combing bidirectional Mendelian randomization. Cardiovasc Diabetol 2025; 24:28. [PMID: 39844252 PMCID: PMC11756161 DOI: 10.1186/s12933-025-02588-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 01/08/2025] [Indexed: 01/24/2025] Open
Abstract
AIM Both clonal hematopoiesis of indeterminate potential (CHIP) and type 2 diabetes mellitus (T2DM) are conditions closely associated with advancing age. This study delves into the possible implications and prognostic significance of CHIP and T2DM in patients diagnosed with ST-segment elevation myocardial infarction (STEMI). METHODS Deep-targeted sequencing employing a unique molecular identifier (UMI) for the analysis of 42 CHIP mutations-achieving an impressive mean depth of coverage at 1000 × -was conducted on a cohort of 1430 patients diagnosed with acute myocardial infarction (473 patients with T2DM and 930 non-DM subjects). Variant allele fraction ≥ 2.0% indicated the presence of CHIP mutations. The association between CHIP and T2DM was evaluated by the comparison of (i) the prevalence of CHIP mutations among individuals with diabetes versus those without, (ii) the clinical characteristics delineated by CHIP mutations within the cohort of diabetic patients and (iii) the prognostic significance and correlation of CHIP mutations with mortality rates in T2DM subjects. Furthermore, a two-sample bidirectional Mendelian randomization study was performed using genetic instruments from the genome-wide association study for TET2 mutation CH from the UK Biobank (UKB) (2041 cases,173,918 controls) to investigate the causal relationship with T2DM from the FinnGen consortium (65,085 cases and 335,112 controls), and vice versa. RESULTS (i) Most commonly CHIP mutations exhibiting a variant allele fraction of ≥ 2.0% were identified in 50/473 (10.6%) patients with T2DM, demonstrating a greater prevalence compared to non-DM subjects [69/930 (7.4%); P < 0.05] across various age groups. (ii) After multivariable adjustment, the mortality of any CHIP mutations were 2.03-fold higher in DM [adjusted hazard ratio (HR) 2.03; 95% confidence interval (CI) 1.07-3.84, P < 0.05]. (iii) In gene-specific analyses, TET2 somatic mutation presented the highest association with mortality among T2DM (adjusted HR 5.24; 95% CI 2.02-13.61, P = 0.001). ASXL1 CHIP mutation which displayed a striking correlation with cardiac death (HR: 3.14; 95% CI 1.24-7.93; P < 0.05) with consistent associations observed among T2DM subgroup (HR: 4.51; 95% CI 1.30-15.6; P < 0.05). (iv) The correlation between PCSK9 and the Tet2-CHIP mutation was observed in both the T2DM cohort (correlation = 0.1215, P = 0.011) and the overall enrolled cohort (correlation = 0.0578, P = 0.0382). (v) Bidirectional Mendelian randomization studies indicated that the development of T2DM increases the propensity for CHIP. However, CHIP does not subsequently accelerate the onset of T2DM. CONCLUSION CHIP mutations, particularly TET2, are more prevalent in patients with T2DM compared to individuals without diabetes. The presence of these mutations is associated with adverse clinical outcomes, notably increased mortality rates. Moreover, bidirectional Mendelian randomization analyses provide supporting evidence for a potential causal relationship between TET2-related CHIP and the development of T2DM.
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Affiliation(s)
- Xiaoxiao Zhao
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College & Chinese Academy of Medical Sciences, No.167, Beijing, 100037, China
| | - Jiannan Li
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College & Chinese Academy of Medical Sciences, No.167, Beijing, 100037, China
| | - Shaodi Yan
- Fuwai Hospital, Chinese Academy of Medical Sciences, 12 Langshan Rd, Shenzhen, 518000, China
| | - Yu Tan
- Department of Cardiovascular Medicine, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Runzhen Chen
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College & Chinese Academy of Medical Sciences, No.167, Beijing, 100037, China
| | - Nan Li
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College & Chinese Academy of Medical Sciences, No.167, Beijing, 100037, China
| | - Jinying Zhou
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China
| | - Chen Liu
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College & Chinese Academy of Medical Sciences, No.167, Beijing, 100037, China
| | - Peng Zhou
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College & Chinese Academy of Medical Sciences, No.167, Beijing, 100037, China
| | - Yi Chen
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College & Chinese Academy of Medical Sciences, No.167, Beijing, 100037, China
| | - Hongbing Yan
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College & Chinese Academy of Medical Sciences, No.167, Beijing, 100037, China.
- Fuwai Hospital, Chinese Academy of Medical Sciences, 12 Langshan Rd, Shenzhen, 518000, China.
| | - Hanjun Zhao
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College & Chinese Academy of Medical Sciences, No.167, Beijing, 100037, China.
| | - Li Song
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College & Chinese Academy of Medical Sciences, No.167, Beijing, 100037, China.
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Jeong Y. Comprehensive analysis of clinical, pathological, and molecular features in chronic myelomonocytic leukemia: frequent ASXL1 and NRAS mutations and higher mutation burden in myeloproliferative CMML compared to myelodysplastic CMML. Leuk Lymphoma 2025:1-10. [PMID: 39819262 DOI: 10.1080/10428194.2025.2453093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 01/07/2025] [Accepted: 01/08/2025] [Indexed: 01/19/2025]
Abstract
Various aspects of myeloproliferative chronic myelomonocytic leukemia (MP-CMML) and myelodysplastic CMML (MD-CMML) have been reported but inconsistencies remain. This study conducted a comprehensive retrospective analysis of clinical, pathological, and molecular data from a cohort of CMML. The results revealed a higher frequency of ASXL1 and NRAS mutations and a greater mutation burden in MP-CMML, characterized by more tier 1 or 2 variants and dominant mutations. Significant genotype-phenotype correlations were observed, including distinct patterns within MD-CMML subgroups. Additionally, NRAS or RUNX1 mutations and an abnormal karyotype were associated with worse overall survival or progression-free survival. These findings underscore the distinct molecular and pathological differences between MP-CMML and MD-CMML, highlighting the more aggressive nature of MP-CMML and the need for tailored treatment strategies.
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Affiliation(s)
- Yoonseo Jeong
- Department of Laboratory Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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36
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Mayerhofer C, Freedman RA, Parsons HA, Partridge AH, Miller PG. Clonal Hematopoiesis in Women With Breast Cancer. J Clin Oncol 2025:JCO2401848. [PMID: 39823557 DOI: 10.1200/jco-24-01848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 11/25/2024] [Accepted: 12/17/2024] [Indexed: 01/19/2025] Open
Abstract
PURPOSE Clonal hematopoiesis (CH) has been associated with a variety of adverse outcomes, most notably hematologic malignancy and ischemic cardiovascular disease. A series of recent studies also suggest that CH may play a role in the outcomes of patients with solid tumors, including breast cancer. Here, we review the clinical and biological data that underlie potential connections between CH, inflammation, and breast cancer, with a focus on the prevalence and impact of clonal hematopoiesis of indeterminate potential in patients with breast cancer. METHODS We summarize data from multiple studies, including a series of cohorts of patients with breast cancer, to assess the prevalence of CH, the relationship between CH and exposure to cytotoxic therapy, and the correlation between CH and breast cancer-specific outcomes. RESULTS Our findings indicate that CH is prevalent among patients with breast cancer, particularly those treated with cytotoxic therapies. However, there are no definitive data to support an association between the presence of CH and breast cancer-specific outcomes. CONCLUSION Current data do not support routine CH testing in patients with breast cancer, nor should the presence of CH influence decisions regarding breast cancer therapy in most patients. However, larger, long-term studies are necessary to further define the implications of CH in patients with breast cancer and guide clinical decision making.
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Affiliation(s)
- Christina Mayerhofer
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, MA
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA
- Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA
| | - Rachel A Freedman
- Harvard Medical School, Boston, MA
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA
| | - Heather A Parsons
- Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA
- Harvard Medical School, Boston, MA
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA
| | - Ann H Partridge
- Harvard Medical School, Boston, MA
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA
| | - Peter G Miller
- Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA
- Harvard Medical School, Boston, MA
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA
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Pasquer H, Kiladjian JJ, Benajiba L. Current myeloproliferative neoplasm scoring systems for clinical practice. Blood 2025; 145:257-276. [PMID: 39476004 DOI: 10.1182/blood.2024025459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 10/12/2024] [Indexed: 01/18/2025] Open
Abstract
ABSTRACT BCR::ABL1-negative myeloproliferative neoplasms (MPNs) are clonal hematologic malignancies that are caused by the proliferation of myeloid cells that harbor a JAK-STAT pathway activating driver mutation. MPN management recommendations are based on the evaluation of different risks to prevent disease evolution-associated events while preserving patients' quality of life. Such risks can be common across all MPNs or specific to each subtype (polycythemia vera [PV], essential thrombocythemia [ET], prefibrotic myelofibrosis [MF], and primary MF). Patients with MF harbor the worse prognosis, and hematopoietic stem cell transplantation (HSCT) is the only curative treatment at the expense of a high rate of morbidity and mortality. Therefore, accurate scoring systems to estimate overall survival are crucial for the management of patients with MF and the selection for HSCT. In PV and ET, the prediction of vascular events is prioritized given their higher incidence and related morbidity and mortality. Finally, quality of life evaluation is important for all subtypes. To predict these risks and adapt MPN therapeutic strategies, clinical risk scores have been developed over the past decades and more recently have incorporated molecular risk factors for more accurate risk stratification. The large number of scoring systems available, combined with disease heterogeneity and the necessity to predict diverse outcomes, make it difficult for clinicians to choose the most appropriate score to evaluate their patients' risk in 2024. Here, we provide an overview of MPN disease evolution-associated event incidence and conduct an exhaustive comparative review of the scoring systems currently available for each risk. Finally, we propose an algorithm for the use of these scores in clinical practice in each MPN subtype.
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Affiliation(s)
- Hélène Pasquer
- Centre d'Investigations Cliniques, INSERM CIC 1427, Hôpital Saint-Louis, Université Paris Cité, Assistance Publique des Hôpitaux de Paris, Paris, France
- INSERM UMR 944, Institut de Recherche Saint-Louis, Paris, France
| | - Jean-Jacques Kiladjian
- Centre d'Investigations Cliniques, INSERM CIC 1427, Hôpital Saint-Louis, Université Paris Cité, Assistance Publique des Hôpitaux de Paris, Paris, France
- INSERM UMR 1131, Institut de Recherche Saint-Louis, Paris, France
| | - Lina Benajiba
- Centre d'Investigations Cliniques, INSERM CIC 1427, Hôpital Saint-Louis, Université Paris Cité, Assistance Publique des Hôpitaux de Paris, Paris, France
- INSERM UMR 944, Institut de Recherche Saint-Louis, Paris, France
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Regan JA, Kwee LC, Nafissi NA, Bick AG, Kraus WE, Natarajan P, Jaiswal S, Shah SH. Clonal Hematopoiesis Associates with Prevalent and Incident Cardiometabolic Disease in High-Risk Individuals. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.01.14.25320566. [PMID: 39867361 PMCID: PMC11759844 DOI: 10.1101/2025.01.14.25320566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Background Clonal hematopoiesis of indeterminate potential (CHIP) is the age-related presence of expanded somatic clones secondary to leukemogenic driver mutations and is associated with cardiovascular (CV) disease and mortality. We sought to evaluate relationships between CHIP with cardiometabolic diseases and incident outcomes in high-risk individuals. Methods CHIP genotyping was performed in 8469 individuals referred for cardiac catheterization at Duke University (CATHGEN study) to identify variants present at a variant allele fraction (VAF) ≥2%. Associations were tested among any CHIP variant, large CHIP clones (VAF ≥10%) and individual CHIP genes with prevalent cardiometabolic traits. Cox proportional hazard models tested CHIP associations with time-to-overall mortality and Fine-Gray analyses tested CHIP associations with incident cardiovascular outcomes. Results We identified 463 CHIP variants in 427 individuals (5.0%) of which 268 (3.2%) harbored large CHIP clones. CHIP and large CHIP were associated with lower odds of obesity (OR 0.79 [95% CI 0.65-0.98], p=0.03; OR 0.76 [95% CI 0.57-0.99], p=0.04, respectively). CHIP was associated with prevalent HF (OR 1.25 [95% CI 1.01 - 1.55], p=0.04; especially for non-DNMT3A CHIP (OR 1.38 [95% CI 1.04-1.82], p=0.02). CHIP was also associated with incident events: Non-DNMT3A CHIP was associated with increased risk of time-to-HF hospitalization (HR 1.29 [95% CI 1.02-1.63], p=0.03). Conclusions In high-risk individuals referred for cardiac catheterization, large CHIP and non-DNTM3A CHIP were associated with obesity, prevalent HF, incident CV events. These findings strengthen the importance of CHIP as a biomarker for CV disease and highlight the contributing risk of large CHIP clones and non-DNMT3A CHIP variants.
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Affiliation(s)
- Jessica A Regan
- Division of Cardiology, Department of Medicine, Duke University, Durham, NC, USA
- Duke Molecular Physiology Institute, Durham, NC, USA
| | | | - Navid A Nafissi
- Division of Cardiology, Department of Medicine, Duke University, Durham, NC, USA
- Duke Molecular Physiology Institute, Durham, NC, USA
| | - Alexander G Bick
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - William E Kraus
- Division of Cardiology, Department of Medicine, Duke University, Durham, NC, USA
- Duke Molecular Physiology Institute, Durham, NC, USA
| | - Pradeep Natarajan
- Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA
- Program in Medical & Population Genetics, Broad Institute of Harvard & MIT, Cambridge, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | - Sidd Jaiswal
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Svati H Shah
- Division of Cardiology, Department of Medicine, Duke University, Durham, NC, USA
- Duke Molecular Physiology Institute, Durham, NC, USA
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Rofes P, Castillo-Manzano C, Menéndez M, Teulé Á, Iglesias S, Munté E, Ramos-Muntada M, Gómez C, Tornero E, Darder E, Montes E, Valle L, Capellá G, Pineda M, Brunet J, Feliubadaló L, Del Valle J, Lázaro C. TP53 germline testing and hereditary cancer: how somatic events and clinical criteria affect variant detection rate. Genome Med 2025; 17:3. [PMID: 39810221 PMCID: PMC11734529 DOI: 10.1186/s13073-025-01429-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 01/03/2025] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND Germline heterozygous pathogenic variants (PVs) in TP53 cause Li-Fraumeni syndrome (LFS), a condition associated with increased risk of multiple tumor types. As the associated cancer risks were refined over time, clinical criteria also evolved to optimize diagnostic yield. The implementation of multi-gene panel germline testing in different clinical settings has led to the identification of TP53 PV carriers outside the classic LFS-associated cancer phenotypes, leading to a broader cancer phenotypic redefinition and to the renaming of the condition as "heritable TP53-related cancer syndrome" (hTP53rc). Germline TP53 variant interpretation is challenging due to the diverse nature of TP53 PVs, variable penetrance of the syndrome, possible occurrence of TP53 somatic mosaicism, and TP53 involvement in clonal hematopoiesis of indeterminate potential (CHIP). Here we aim to assess the relevance and impact of these issues on the diagnostic routine, and to evaluate the sensitivity of the different LFS clinical criteria to identify hTP53rc. METHODS TP53 was analyzed in 6161 suspected hereditary cancer non-related patients categorized into three subgroups: (1) 495 patients fulfilling any LFS/Chompret clinical criteria; (2) 2481 patients diagnosed with early-onset breast/colorectal cancer; (3) 3185 patients without clinical criteria suggestive of hTP53rc. Ancillary tests were performed when TP53 PVs were identified in individuals not meeting LFS/Chompret criteria and/or when the variant was identified at low variant allele frequency (VAF). RESULTS TP53 PVs were identified in blood DNA of 45 probands. Variant origin was elucidated in 39 of these: 72% patients had a constitutional PV, 10% were mosaics, and 18% had CHIP-associated PVs. Notably, two of the seven CHIP-TP53 PVs identified were detected at high allelic frequencies (VAF > 35%). Twenty-nine percent of germline TP53 PV did not meet any of the LFS clinical criteria. Among the clinical criteria, Chompret 2009 showed the highest sensitivity in our cohort (68% vs. 54% for Chompret 2015), highlighting the relevance of considering lung cancer in the criteria. CONCLUSIONS Our data supports performing TP53 ancillary testing for the identification of potential mosaicisms and CHIP-associated PVs, particularly in patients not meeting clinical criterial for LFS, irrespective of the VAF, and the application of clinical criteria that include lung cancer diagnosis.
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Affiliation(s)
- Paula Rofes
- Hereditary Cancer Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Av. Gran Via 199-203, L'Hospitalet del Llobregat, 08908, Spain
- Hereditary Cancer Program, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Carmen Castillo-Manzano
- Hereditary Cancer Program, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Spain
- Doctoral Programme of Genetics, University of Barcelona, Barcelona, Spain
| | - Mireia Menéndez
- Hereditary Cancer Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Av. Gran Via 199-203, L'Hospitalet del Llobregat, 08908, Spain
- Hereditary Cancer Program, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Álex Teulé
- Hereditary Cancer Program, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Spain
| | - Sílvia Iglesias
- Hereditary Cancer Program, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Spain
| | - Elisabet Munté
- Hereditary Cancer Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Av. Gran Via 199-203, L'Hospitalet del Llobregat, 08908, Spain
- Hereditary Cancer Program, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Mireia Ramos-Muntada
- Hereditary Cancer Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Av. Gran Via 199-203, L'Hospitalet del Llobregat, 08908, Spain
- Hereditary Cancer Program, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Carolina Gómez
- Hereditary Cancer Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Av. Gran Via 199-203, L'Hospitalet del Llobregat, 08908, Spain
- Hereditary Cancer Program, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Spain
| | - Eva Tornero
- Hereditary Cancer Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Av. Gran Via 199-203, L'Hospitalet del Llobregat, 08908, Spain
- Hereditary Cancer Program, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Esther Darder
- Hereditary Cancer Program, Catalan, Institute of Oncology - Institut d'Investigació Biomèdica de Girona (IDIBGi), Girona, Spain
| | - Eva Montes
- Hereditary Cancer Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Av. Gran Via 199-203, L'Hospitalet del Llobregat, 08908, Spain
- Hereditary Cancer Program, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Spain
| | - Laura Valle
- Hereditary Cancer Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Av. Gran Via 199-203, L'Hospitalet del Llobregat, 08908, Spain
- Hereditary Cancer Program, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Gabriel Capellá
- Hereditary Cancer Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Av. Gran Via 199-203, L'Hospitalet del Llobregat, 08908, Spain
- Hereditary Cancer Program, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Marta Pineda
- Hereditary Cancer Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Av. Gran Via 199-203, L'Hospitalet del Llobregat, 08908, Spain
- Hereditary Cancer Program, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Joan Brunet
- Hereditary Cancer Program, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Hereditary Cancer Program, Catalan, Institute of Oncology - Institut d'Investigació Biomèdica de Girona (IDIBGi), Girona, Spain
| | - Lidia Feliubadaló
- Hereditary Cancer Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Av. Gran Via 199-203, L'Hospitalet del Llobregat, 08908, Spain
- Hereditary Cancer Program, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Jesús Del Valle
- Hereditary Cancer Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Av. Gran Via 199-203, L'Hospitalet del Llobregat, 08908, Spain
- Hereditary Cancer Program, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Conxi Lázaro
- Hereditary Cancer Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Av. Gran Via 199-203, L'Hospitalet del Llobregat, 08908, Spain.
- Hereditary Cancer Program, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
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Pershad Y, Uddin MM, Xue L, Haessler J, Collins JM, Mack TM, Glick E, Glaser V, Zhao K, Jaiswal S, Manson JE, Pandey U, Desai P, Natarajan P, Honigberg MC, Kooperberg C, Whitsel EA, Kitzman JO, Bick AG, Reiner AP. Correlates and Consequences of Clonal Hematopoiesis Expansion Rate: A 15-Year Longitudinal Study of 6,986 Women. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.01.12.25320422. [PMID: 39867366 PMCID: PMC11759600 DOI: 10.1101/2025.01.12.25320422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased mortality and malignancy risk, yet the determinants of clonal expansion remain poorly understood. We performed sequencing at >4,000x depth of coverage for CHIP mutations in 6,986 postmenopausal women from the Women's Health Initiative at two timepoints approximately 15 years apart. Among 3,685 mutations detected at baseline (VAF ≥ 0.5%), 50% progressed to CHIP (VAF ≥ 2%) at follow-up. We confirmed that clonal expansion is highly dependent on initial clone size and CHIP driver gene, with SF3B1 and JAK2 mutations exhibiting the fastest growth rate. We identified germline variants in TERT , IL6R , TCL1A , and MSI2 that modulate clonal expansion rate. Measured baseline leukocyte telomere length showed differential effects on incident CHIP risk, with shorter baseline leukocyte telomere length predisposing to incident PPM1D mutations and longer baseline leukocyte telomere length favoring incident DNMT3A mutations. We discovered that the IL6R missense variant p.Asp358Ala specifically impairs TET2 clonal expansion, supported by direct measurements of soluble interleukin-6 receptor and interleukin-6. Faster clonal growth rate was associated with increased risk of cytopenia, leukemia, and all-cause mortality. Notably, CHIP clonal expansion rate mediated 34.4% and 43.7% of the Clonal Hematopoiesis Risk Score's predictive value for leukemia and all-cause mortality, respectively. These findings reveal key biological determinants of CHIP progression and suggest that incorporating growth rate measurements could enhance risk stratification.
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Polomski EAS, Heemelaar JC, de Ronde MES, Al Jaff AAM, Mertens BJA, van Dijkman PRM, Jukema JW, Antoni ML. Increased prevalence of coronary atherosclerosis in cancer survivors: A retrospective matched cross-sectional study with coronary CT angiography. Am Heart J 2025; 282:134-145. [PMID: 39793723 DOI: 10.1016/j.ahj.2025.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 12/16/2024] [Accepted: 01/06/2025] [Indexed: 01/13/2025]
Abstract
BACKGROUND Cancer and cancer treatment may accelerate the development of cardiovascular disease. With the improved prognosis of cancer survivors, cardiovascular events are increasing in this patient group. However, it is unknown whether the prevalence of coronary atherosclerosis is increased in patients with a history of cancer. This study aims to evaluate the prevalence and severity of coronary atherosclerosis in different age groups of cancer survivors compared to matched controls. METHODS Consecutive cancer survivors aged > 30 years who underwent evaluation for stable coronary artery disease with coronary computed tomography angiography (CCTA) were included in this retrospective study. Propensity score matching was performed and cancer survivors were matched 1:2 to a control population without oncological history. The presence of coronary atherosclerosis was assessed in both groups. RESULTS The study population consisted of 312 cancer survivors and 624 matched controls. Median age at CCTA scan was 59.2 [50.3-67.5] years and 66.0% was female. Coronary atherosclerosis was observed in 257 (82.4%) cancer survivors compared to 459 (73.6%) control patients with an Odds Ratio (OR) of 1.68 [95% CI: 1.19-2.36], P = .003. Mainly younger cancer survivors aged between 30 and 59 years had an increased prevalence of coronary atherosclerosis with an OR of 2.21 [95% CI: 1.40-3.49] compared to control patients (P = .001). In addition, thoracic radiotherapy showed a significant association with increased prevalence of atherosclerosis in the younger population with an OR of 3.29 ([95% CI: 1.70-6.38], P < .001). CONCLUSIONS Patients with a history cancer have an increased prevalence of coronary atherosclerosis on CCTA compared to matched patients without cancer. This effect was most pronounced in younger patients aged 30 to 59 years.
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Affiliation(s)
- Elissa A S Polomski
- Department of Cardiology, Heart Lung Center, Leiden University Medical Center, Leiden, The Netherlands
| | - Julius C Heemelaar
- Department of Cardiology, Heart Lung Center, Leiden University Medical Center, Leiden, The Netherlands
| | - Mian E S de Ronde
- Department of Cardiology, Heart Lung Center, Leiden University Medical Center, Leiden, The Netherlands
| | - Ahmed A M Al Jaff
- Department of Cardiology, Heart Lung Center, Leiden University Medical Center, Leiden, The Netherlands
| | - B J A Mertens
- Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
| | - Paul R M van Dijkman
- Department of Cardiology, Heart Lung Center, Leiden University Medical Center, Leiden, The Netherlands
| | - J Wouter Jukema
- Department of Cardiology, Heart Lung Center, Leiden University Medical Center, Leiden, The Netherlands; Netherlands Heart Institute, Utrecht, The Netherlands
| | - M Louisa Antoni
- Department of Cardiology, Heart Lung Center, Leiden University Medical Center, Leiden, The Netherlands.
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Jabbour EJ, Rousselot P, Gokbuget N, Chevallier P, Kantarjian HM, Stelljes M. Inotuzumab Ozogamicin as First-Line Therapy in Acute Lymphoblastic Leukemia. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2025:S2152-2650(24)02466-2. [PMID: 39909815 DOI: 10.1016/j.clml.2024.12.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 12/18/2024] [Accepted: 12/27/2024] [Indexed: 02/07/2025]
Abstract
The long-term outcome of older patients with acute lymphoblastic leukemia (ALL) is poor due to a reduced ability to tolerate intensive chemotherapy, a more aggressive disease biology, and the presence of comorbidities. Older adults with Philadelphia chromosome-negative (Ph-) B-cell ALL have the highest rates of treatment failure and complications, and the pediatric-inspired regimens that are effective in younger adults are severely limited by their toxicity in older patients. Targeted therapies, including inotuzumab ozogamicin (InO) and blinatumomab, have potent activity in B-cell ALL and are used today as single agents, and in combination with chemotherapy in both salvage and frontline ALL therapy. Optimized frontline use of B-cell targeting agents would potentially reduce the need for, and exposure to, conventional chemotherapy and improve the tolerance and efficacy of reduced-intensity chemotherapy regimens combined with targeted therapies. This review summarizes the efficacy and safety results of several recent trials investigating different approaches with InO as first-line therapy in patients with Ph- B-cell ALL.
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Affiliation(s)
- Elias J Jabbour
- Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, Houston, TX.
| | - Philippe Rousselot
- Department of Hematology, Centre Hospitalier de Versailles, University Versailles Paris-Saclay, France
| | - Nicola Gokbuget
- Department of Medicine II, Hematology/Oncology, Goethe University, University Hospital, Frankfurt, Germany
| | | | - Hagop M Kantarjian
- Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, Houston, TX
| | - Matthias Stelljes
- Department of Medicine A, Hematology, Oncology, Hemostaseology and Pneumology, University Hospital Münster, Münster, Germany
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Sum H, Brewer AC. The Impact of Modifiable Risk Factors on the Endothelial Cell Methylome and Cardiovascular Disease Development. FRONT BIOSCI-LANDMRK 2025; 30:26082. [PMID: 39862076 DOI: 10.31083/fbl26082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 08/29/2024] [Accepted: 09/11/2024] [Indexed: 01/27/2025]
Abstract
Cardiovascular disease (CVD) is the most prevalent cause of mortality and morbidity in the Western world. A common underlying hallmark of CVD is the plaque-associated arterial thickening, termed atherosclerosis. Although the molecular mechanisms underlying the aetiology of atherosclerosis remain unknown, it is clear that both its development and progression are associated with significant changes in the pattern of DNA methylation within the vascular cell wall. The endothelium is the major regulator of vascular homeostasis, and endothelial cell dysfunction (ED) is considered an early marker for atherosclerosis. Thus, it is speculated that changes in DNA methylation within endothelial cells may, in part, be causal in ED, leading to atherosclerosis and CVD generally. This review will evaluate the extensive evidence that environmental risk factors, known to be associated with atherosclerosis, such as diabetes, metabolic disorder, smoking, hypertension and hypercholesterolaemia etc. can affect the methylome of the endothelium and consequently act to alter gene transcription and function. Further, the potential mechanisms whereby such risk factors might impact upon the activities and/or specificities of the epigenetic writers and erasers which determine the methylome [the DNA methyl transferases (DNMTs) and Ten Eleven translocases (TETs)] are considered here. Notably, the TET proteins are members of the 2-oxoglutarate-dependent dioxygenase superfamily which require molecular oxygen (O2) and α-ketoglutarate (α-KG) as substrates and iron-2+ (Fe II) as a cofactor. This renders their activities subject to modulation by hypoxia, metabolic flux and cellular redox. The potential significance of this, with respect to the impact of modifiable risk factors upon the activities of the TETs and the methylome of the endothelium is discussed.
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Affiliation(s)
- Hashum Sum
- School of Cardiovascular and Metabolic Medicine & Sciences, British Heart Foundation Centre of Research Excellence, King's College London, SE5 9NU London, UK
| | - Alison C Brewer
- School of Cardiovascular and Metabolic Medicine & Sciences, British Heart Foundation Centre of Research Excellence, King's College London, SE5 9NU London, UK
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Li X, Wang J, Hu L, Cheng T. How age affects human hematopoietic stem and progenitor cells and the strategies to mitigate aging. Exp Hematol 2025; 143:104711. [PMID: 39788412 DOI: 10.1016/j.exphem.2025.104711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 12/29/2024] [Accepted: 12/30/2024] [Indexed: 01/12/2025]
Abstract
Hematopoietic stem cells (HSCs) are central to blood formation and play a pivotal role in hematopoietic and systemic aging. With aging, HSCs undergo significant functional changes, such as an increased stem cell pool, declined homing and reconstitution capacity, and skewed differentiation toward myeloid and megakaryocyte/platelet progenitors. These phenotypic alterations are likely due to the expansion of certain clones, known as clonal hematopoiesis (CH), which leads to disrupted hematopoietic homeostasis, including anemia, impaired immunity, higher risks of hematological malignancies, and even associations with cardiovascular disease, highlighting the broader impact of HSC aging on overall health. HSC aging is driven by a range of mechanisms involving both intrinsic and extrinsic factors, such as DNA damage accumulation, epigenetic remodeling, inflammaging and metabolic regulation. In this review, we summarize the updated understanding of age-related changes in hematopoietic stem and progenitor cells (HSPCs) and the mechanisms underlying the aging process in mammalian models, especially in human study. Additionally, we provide insights into potential therapeutic strategies to counteract aging process and enhance HSC regenerative capacity, which will support therapeutic interventions and promote healthy aging.
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Affiliation(s)
- Xueling Li
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin, China
| | - Jianwei Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin, China
| | - Linping Hu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin, China.
| | - Tao Cheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin, China.
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Esai Selvan M, Nathan DI, Guisado D, Collatuzzo G, Iruvanti S, Boffetta P, Mascarenhas J, Hoffman R, Cohen LJ, Marcellino BK, Gümüş ZH. Clonal Hematopoiesis of Indeterminate Potential in Crohn's Disease and Ulcerative Colitis. Inflamm Bowel Dis 2025:izae312. [PMID: 39761417 DOI: 10.1093/ibd/izae312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Indexed: 01/15/2025]
Abstract
BACKGROUND Clonal hematopoiesis of indeterminate potential (CHIP) is the presence of somatic mutations in myeloid and lymphoid malignancy genes in the blood cells of individuals without a hematologic malignancy. Inflammation is hypothesized to be a key mediator in the progression of CHIP to hematologic malignancy and patients with CHIP have a high prevalence of inflammatory diseases. This study aimed to identify the prevalence and characteristics of CHIP in patients with inflammatory bowel disease (IBD). METHODS We analyzed whole-exome sequencing data from 587 Crohn's disease (CD), 441 ulcerative colitis (UC), and 293 non-IBD controls to assess CHIP prevalence and used logistic regression to study associations with clinical outcomes. RESULTS Older UC patients (age > 45) harbored increased myeloid-CHIP mutations compared to younger patients (age ≤ 45) (P = .01). Lymphoid-CHIP was more prevalent in older IBD patients (P = .007). Young CD patients were found to have myeloid-CHIP with high-risk features. Inflammatory bowel disease patients with CHIP exhibited unique mutational profiles compared to controls. Steroid use was associated with increased CHIP (P = .05), while anti-TNF therapy was associated with decreased myeloid-CHIP (P = .03). Pathway enrichment analyses indicated an overlap between CHIP genes, IBD phenotypes, and inflammatory pathways. CONCLUSIONS Our findings underscore a connection between IBD and CHIP pathophysiology. Patients with IBD and CHIP had unique risk profiles, especially among older UC patients and younger CD patients. These findings suggest distinct evolutionary pathways for CHIP in IBD and necessitate awareness among IBD providers and hematologists to identify patients potentially at risk for CHIP-related complications including malignancy, cardiovascular disease, and acceleration of their inflammatory disease.
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Affiliation(s)
- Myvizhi Esai Selvan
- Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, Box 1498, New York, NY 10029, USA
| | - Daniel I Nathan
- Tisch Cancer Institute, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, Box 1079, New York, NY 10029, USA
| | - Daniela Guisado
- Division of Pediatric Gastroenterology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, Box 1069, New York, NY 10029, USA
| | - Giulia Collatuzzo
- Department of Medical and Surgical Sciences, University of Bologna, Via Zamboni, 33 - 40126, Bologna, Italy
| | - Sushruta Iruvanti
- Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, Box 1498, New York, NY 10029, USA
| | - Paolo Boffetta
- Department of Medical and Surgical Sciences, University of Bologna, Via Zamboni, 33 - 40126, Bologna, Italy
- Stony Brook Department of Family, Population and Preventive Medicine, Renaissance School of Medicine, 101 Nicolls Road Health Sciences Center, Level 4, Stony Brook, NY 11794, USA
| | - John Mascarenhas
- Tisch Cancer Institute, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, Box 1079, New York, NY 10029, USA
| | - Ronald Hoffman
- Tisch Cancer Institute, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, Box 1079, New York, NY 10029, USA
| | - Louis J Cohen
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, Box 1069, New York, NY 10029, USA
| | - Bridget K Marcellino
- Tisch Cancer Institute, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, Box 1079, New York, NY 10029, USA
| | - Zeynep H Gümüş
- Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, Box 1498, New York, NY 10029, USA
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, Box 1630, New York, NY 10029, USA
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Yang S, Penna V, Lavine KJ. Functional diversity of cardiac macrophages in health and disease. Nat Rev Cardiol 2025:10.1038/s41569-024-01109-8. [PMID: 39743564 DOI: 10.1038/s41569-024-01109-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/21/2024] [Indexed: 01/04/2025]
Abstract
Macrophages make up a substantial portion of the stromal compartment of the heart in health and disease. In the past decade, the origins of these cardiac macrophages have been established as two broad populations derived from either embryonic or definitive haematopoiesis and that can be distinguished by the expression of CC-motif chemokine receptor 2 (CCR2). These cardiac macrophage populations are transcriptionally distinct and have differing cell surface markers and divergent roles in cardiac homeostasis and disease. Embryonic-derived CCR2- macrophages are a tissue-resident population that participates in tissue development, repair and maintenance, whereas CCR2+ macrophages are derived from definitive haematopoiesis and contribute to inflammation and tissue damage. Studies from the past 5 years have leveraged single-cell RNA sequencing technologies to expand our understanding of cardiac macrophage diversity, particularly of the monocyte-derived macrophage populations that reside in the injured and diseased heart. Emerging technologies in spatial transcriptomics have enabled the identification of distinct disease-associated cellular neighbourhoods consisting of macrophages, other immune cells and fibroblasts, highlighting the involvement of macrophages in cell-cell communication. Together, these discoveries lend new insights into the role of specific macrophage populations in the pathogenesis of cardiac disease, which can pave the way for the identification of new therapeutic targets and the development of diagnostic tools. In this Review, we discuss the developmental origin of cardiac macrophages and describe newly identified cell states and associated cellular neighbourhoods in the steady state and injury settings. We also discuss various contributions and effector functions of cardiac macrophages in homeostasis and disease.
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Affiliation(s)
- Steven Yang
- Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA
| | - Vinay Penna
- Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA
| | - Kory J Lavine
- Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA.
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA.
- Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO, USA.
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Supriami K, Urbut SM, Tello-Ayala JR, Unlu O, Friedman SF, Abou-Karam R, Koyama S, Uddin MM, Pomerantsev E, Lu MT, Honigberg MC, Aragam KG, Doshi-Velez F, Patel AP, Natarajan P, Ellinor PT, Fahed AC. Genomic Drivers of Coronary Artery Disease and Risk of Future Outcomes After Coronary Angiography. JAMA Netw Open 2025; 8:e2455368. [PMID: 39836422 PMCID: PMC11751748 DOI: 10.1001/jamanetworkopen.2024.55368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 11/11/2024] [Indexed: 01/22/2025] Open
Abstract
Importance Disease characteristics of genetically mediated coronary artery disease (CAD) on coronary angiography and the association of genomic risk with outcomes after coronary angiography are not well understood. Objective To assess the angiographic characteristics and risk of post-coronary angiography outcomes of patients with genomic drivers of CAD: familial hypercholesterolemia (FH), high polygenic risk score (PRS), and clonal hematopoiesis of indeterminate potential (CHIP). Design, Setting, and Participants A retrospective cohort study of 3518 Mass General Brigham Biobank participants with genomic information who underwent coronary angiography was conducted between July 18, 2000, and August 1, 2023. Exposures The presence of a genomic risk factor of CAD, defined as FH variant, high CAD PRS, or CHIP driver variation. Main Outcomes and Measures Coronary artery disease presentation (stable or acute), angiographic CAD characteristics (severity and burden), angiographic outcomes (repeat angiogram, revascularization, and in-stent restenosis), and clinical outcomes (heart failure and all-cause mortality). Results Among 3518 participants (2467 [70.1%] male; median age, 64.0 [IQR, 55.0-72.0] years), 1509 (42.9%) had at least 1 genomic driver of CAD (26 FH, 1191 high CAD PRS, and 466 CHIP) that was associated with the presentation of acute coronary syndromes (adjusted odds ratio, 2.67; 95% CI, 2.19-3.26) and with the presence, burden, and severity of angiographic CAD. This association was driven by FH and CAD PRS. One SD of CAD PRS was associated with a 12.51-point higher Gensini score. During 9 years of follow-up, there was an increased risk among FH carriers for a repeat angiogram (adjusted hazard ratio [AHR], 1.70; 95% CI, 1.02-2.83), and revascularization (AHR, 1.97; 95% CI, 1.02-3.80), and among people with high CAD PRS (repeat angiogram: AHR, 1.79; 95% CI, 1.45-2.22; revascularization: AHR, 1.85; 95% CI, 1.37-2.50; and in-stent restenosis: AHR, 3.89; 95% CI, 2.16-7.01). CHIP carriers had no significant increase in angiographic outcomes but were at higher risk of heart failure (AHR, 1.58; 95% CI, 1.04-2.40) and all-cause mortality (AHR, 1.78; 95% CI, 1.47-2.16). Conclusions and Relevance The findings of this study suggest that germline monogenic and polygenic risk are associated with acute coronary syndromes presentation, severity and burden of atherosclerosis, and risk of repeat angiogram, revascularization, and in-stent restenosis. CHIP variant status is associated with incident heart failure and mortality after coronary angiography.
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Affiliation(s)
- Kelvin Supriami
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Division of Cardiology, Massachusetts General Hospital, Boston
| | - Sarah M. Urbut
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Division of Cardiology, Massachusetts General Hospital, Boston
| | - José R. Tello-Ayala
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Division of Cardiology, Massachusetts General Hospital, Boston
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts
| | - Ozan Unlu
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Division of Cardiology, Brigham and Women’s Hospital, Boston, Massachusetts
- Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts
| | - Samuel F. Friedman
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Division of Cardiology, Massachusetts General Hospital, Boston
| | - Roukoz Abou-Karam
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Division of Cardiology, Massachusetts General Hospital, Boston
| | - Satoshi Koyama
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Division of Cardiology, Massachusetts General Hospital, Boston
| | - Md Mesbah Uddin
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Division of Cardiology, Massachusetts General Hospital, Boston
| | - Eugene Pomerantsev
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Division of Cardiology, Massachusetts General Hospital, Boston
| | - Michael T. Lu
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Cardiovascular Imaging Research Center, Department of Radiology, Massachusetts General Hospital & Harvard Medical School, Boston
| | - Michael C. Honigberg
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Division of Cardiology, Massachusetts General Hospital, Boston
- Center for Genomic Medicine, Massachusetts General Hospital, Boston
| | - Krishna G. Aragam
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Division of Cardiology, Massachusetts General Hospital, Boston
| | - Finale Doshi-Velez
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts
| | - Aniruddh P. Patel
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Division of Cardiology, Massachusetts General Hospital, Boston
- Center for Genomic Medicine, Massachusetts General Hospital, Boston
| | - Pradeep Natarajan
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Division of Cardiology, Massachusetts General Hospital, Boston
- Center for Genomic Medicine, Massachusetts General Hospital, Boston
- Personalized Medicine, Mass General Brigham, Boston, Massachusetts
| | - Patrick T. Ellinor
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Division of Cardiology, Massachusetts General Hospital, Boston
| | - Akl C. Fahed
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Division of Cardiology, Massachusetts General Hospital, Boston
- Center for Genomic Medicine, Massachusetts General Hospital, Boston
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Calvillo-Argüelles O, Vanner RJ. Heart Failure Post-Hematopoietic Cell Transplantation in Patients With Lymphoma: Another Piece of the CHIP Puzzle. JACC CardioOncol 2025; 7:34-37. [PMID: 39896119 PMCID: PMC11782005 DOI: 10.1016/j.jaccao.2024.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2025] Open
Affiliation(s)
- Oscar Calvillo-Argüelles
- Division of Clinical Sciences, NOSM University, Sudbury, Ontario, Canada
- Department of Cardiology, Department of Medical Oncology, Health Sciences North, Sudbury, Ontario, Canada
- NeoHealth Heart Team, Sudbury, Ontario, Canada
| | - Robert J. Vanner
- Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
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Shaban D, Najm N, Droin L, Nijnik A. Hematopoietic Stem Cell Fates and the Cellular Hierarchy of Mammalian Hematopoiesis: from Transplantation Models to New Insights from in Situ Analyses. Stem Cell Rev Rep 2025; 21:28-44. [PMID: 39222178 DOI: 10.1007/s12015-024-10782-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/17/2024] [Indexed: 09/04/2024]
Abstract
Hematopoiesis is the process that generates the cells of the blood and immune system from hematopoietic stem and progenitor cells (HSPCs) and represents the system with the most rapid cell turnover in a mammalian organism. HSPC differentiation trajectories, their underlying molecular mechanisms, and their dysfunctions in hematologic disorders are the focal research questions of experimental hematology. While HSPC transplantations in murine models are the traditional tool in this research field, recent advances in genome editing and next generation sequencing resulted in the development of many fundamentally new approaches for the analyses of mammalian hematopoiesis in situ and at single cell resolution. The current review will cover many recent developments in this field in murine models, from the bulk lineage tracing studies of HSPC differentiation to the barcoding of individual HSPCs with Cre-recombinase, Sleeping Beauty transposase, or CRISPR/Cas9 tools, to map hematopoietic cell fates, together with their transcriptional and epigenetic states. We also address studies of the clonal dynamics of human hematopoiesis, from the tracing of HSPC clonal behaviours based on viral integration sites in gene therapy patients to the recent analyses of unperturbed human hematopoiesis based on naturally accrued mutations in either nuclear or mitochondrial genomes. Such studies are revolutionizing our understanding of HSPC biology and hematopoiesis both under homeostatic conditions and in the response to various forms of physiological stress, reveal the mechanisms responsible for the decline of hematopoietic function with age, and in the future may advance the understanding and management of the diverse disorders of hematopoiesis.
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Affiliation(s)
- Dania Shaban
- Department of Physiology, McGill University, 368 Bellini Life Sciences Complex, 3649 Promenade Sir William Osler, Montreal, QC, H3G 0B1, Canada
- McGill University Research Centre on Complex Traits, McGill University, Montreal, QC, Canada
| | - Nay Najm
- Department of Physiology, McGill University, 368 Bellini Life Sciences Complex, 3649 Promenade Sir William Osler, Montreal, QC, H3G 0B1, Canada
- McGill University Research Centre on Complex Traits, McGill University, Montreal, QC, Canada
| | - Lucie Droin
- Department of Physiology, McGill University, 368 Bellini Life Sciences Complex, 3649 Promenade Sir William Osler, Montreal, QC, H3G 0B1, Canada
- McGill University Research Centre on Complex Traits, McGill University, Montreal, QC, Canada
| | - Anastasia Nijnik
- Department of Physiology, McGill University, 368 Bellini Life Sciences Complex, 3649 Promenade Sir William Osler, Montreal, QC, H3G 0B1, Canada.
- McGill University Research Centre on Complex Traits, McGill University, Montreal, QC, Canada.
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50
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Locher BN, Löwe P, Christen F, Damm F. Detection and Characterization of Clonal Hematopoiesis. Methods Mol Biol 2025; 2865:449-474. [PMID: 39424737 DOI: 10.1007/978-1-0716-4188-0_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2024]
Abstract
Clonal hematopoiesis (CH) is the age-related expansion of hematopoietic stem cell clones resulting from the acquisition of somatic point mutations or mosaic chromosomal alterations (mCAs). It is linked to adverse systemic effects, including hematologic malignancies, cardiovascular diseases, metabolic disorders, as well as liver and kidney ailments, ultimately contributing to elevated overall mortality.Given its diverse biological and clinical implications, the identification of clonal hematopoiesis holds significance in various contexts. While traditionally centered on mutations associated with myeloid malignancies, stem/progenitor cell involvement has been documented for various lymphoid malignancies, including T-cell lymphoma, chronic lymphocytic leukemia (CLL), and follicular lymphoma (FL). Lymphoid CH (L-CH) involves a broader spectrum of genes and occurs at a lower prevalence, resulting in reduced mutation prevalences per gene. This characteristic poses challenges for efficient CH detection.The major strategies to identify CH are whole exome sequencing (WES), whole genome sequencing (WGS), or targeted sequencing. Targeted sequencing allows for much higher sequencing depth compared to WES and WGS because of the focus on genes known to be associated with CH and therefore allows detecting potential variants at low frequencies with high precision. Here, we describe an error-corrected targeted sequencing approach for detection of CH in bone marrow (BM) or peripheral blood (PB) samples, which we have successfully established and used in various cohorts. This protocol includes the process of DNA isolation from PB and BM samples, library preparation with molecular tags including quality control steps and computational analysis including variant filtering.
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Affiliation(s)
- Benjamin N Locher
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology, Berlin, Germany
| | - Pelle Löwe
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology, Berlin, Germany
| | - Friederike Christen
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology, Berlin, Germany
| | - Frederik Damm
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology, Berlin, Germany.
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
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