|
1
|
Nagao K, Watanuki M, Hayashi H, Kawamata N, Kuroiwa K, Narita H, Okamura R, Shimada S, Arai N, Kawaguchi Y, Yanagisawa K, Hattori N. Clinical impact of donor telomere length after umbilical cord blood transplantation. Cytotherapy 2025; 27:626-632. [PMID: 39918489 DOI: 10.1016/j.jcyt.2025.01.011] [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: 12/01/2024] [Revised: 01/10/2025] [Accepted: 01/21/2025] [Indexed: 05/24/2025]
Abstract
BACKGROUND AND AIMS Several studies have shown that the telomere length of engrafted donor cells affects the clinical outcomes in patients with hematologic diseases after allogeneic stem-cell transplantation (allo-SCT). However, the relationship between donor telomere length and clinical outcomes after umbilical-cord blood transplantation (UCBT) remains unknown. The study aim was to assess the relationship between donor telomere length and transplantation outcomes. METHODS We measured donor-derived relative telomere length (RTL) in 75 patients after single-unit UCBT and evaluated the association between telomere length and transplantation outcomes. RESULTS Compared with patients with shorter RTL, patients with longer RTL had a higher risk of bacterial and bloodstream infections [hazard ratio (HR), 4.79; 95% confidence interval (CI), 1.70-13.46; P = 0.003 and HR, 3.43; 95% CI, 1.19-9.82; P = 0.022, respectively] and was possibly associated with reduced relapse (HR 0.44, 95% CI 0.15-1.27, P = 0.13) by multivariate analysis. CONCLUSIONS Patients after UCBT who received engrafted donor cells with longer RTL had a higher risk of bacterial and bloodstream infections. The measured donor-derived RTL at engraftment after UCBT may predict clinical outcomes.
Collapse
Affiliation(s)
- Kazuki Nagao
- Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Megumi Watanuki
- Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Hidenori Hayashi
- Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Natsuki Kawamata
- Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Kai Kuroiwa
- Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Hinako Narita
- Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Reiko Okamura
- Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Shotaro Shimada
- Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Nana Arai
- Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Yukiko Kawaguchi
- Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Kouji Yanagisawa
- Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Norimichi Hattori
- Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
| |
Collapse
|
|
2
|
Hong Y, Lee JM, Lee C, Na D, Jung J, Ahn A, Yoo JW, Lee JW, Chung NG, Kim M, Kim Y. Telomere Length and Genetic Variations in Acquired Pediatric Aplastic Anemia: A Flow-FISH Study in Korean Patients. Diagnostics (Basel) 2025; 15:931. [PMID: 40218281 PMCID: PMC11988933 DOI: 10.3390/diagnostics15070931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Accepted: 03/31/2025] [Indexed: 04/14/2025] Open
Abstract
Background: Aplastic anemia (AA) is a rare bone marrow failure syndrome characterized by notably short telomere length, which is associated with treatment responses. In this study, we measured telomere lengths in Korean pediatric AA patients using flow-fluorescence in situ hybridization (Flow-FISH) and explored their shortening in relation to disease characteristics, genetic conditions and patient outcomes. Methods: We analyzed peripheral blood samples from 75 AA patients and 101 healthy controls. Telomere lengths were measured using Flow-FISH, and relative telomere length (RTL) and delta RTL assessments were conducted. Genetic evaluations included karyotyping, chromosome breakage tests and clinical exome sequencing (CES) to identify inherited bone marrow failure syndrome (IBMFS)-associated genetic variants. Results: Telomere lengths in AA patients were significantly lower than those of age-adjusted healthy controls. Patients receiving immunosuppressive therapy tended to have long telomeres, as indicated by high delta RTL values. Patients with genetic abnormalities, including karyotype abnormalities (n = 2) and genetic variants (n = 11) such as carrier genes of IBMFS or variants of unclear significance, showed significantly short telomere lengths. Conclusions: This study reinforces the importance of telomere length as a biomarker in acquired AA. Utilizing Flow-FISH, we were able to accurately measure telomere lengths and establish confidence in this method as an appropriate laboratory test. We found significant reduction in telomere lengths in AA patients, and importantly, longer telomeres were correlated with better outcomes in immunosuppressive therapy. Additionally, our genetic analysis underscored the relevance of variants in IBMFS-associated genes to the pathophysiology of short telomeres.
Collapse
Affiliation(s)
- Yuna Hong
- Catholic Genetic Laboratory Center, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (Y.H.); (J.-M.L.); (C.L.); (D.N.); (Y.K.)
- Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Jong-Mi Lee
- Catholic Genetic Laboratory Center, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (Y.H.); (J.-M.L.); (C.L.); (D.N.); (Y.K.)
- Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
| | - Chaeyeon Lee
- Catholic Genetic Laboratory Center, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (Y.H.); (J.-M.L.); (C.L.); (D.N.); (Y.K.)
- Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Duyeon Na
- Catholic Genetic Laboratory Center, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (Y.H.); (J.-M.L.); (C.L.); (D.N.); (Y.K.)
- Department of Medical Sciences, Graduate School of The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Jin Jung
- Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
| | - Ari Ahn
- Department of Laboratory Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
| | - Jae Won Yoo
- Department of Pediatrics, Catholic Hematology Hospital, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (J.W.Y.); (J.W.L.)
| | - Jae Wook Lee
- Department of Pediatrics, Catholic Hematology Hospital, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (J.W.Y.); (J.W.L.)
| | - Nack-Gyun Chung
- Department of Pediatrics, Catholic Hematology Hospital, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (J.W.Y.); (J.W.L.)
| | - Myungshin Kim
- Catholic Genetic Laboratory Center, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (Y.H.); (J.-M.L.); (C.L.); (D.N.); (Y.K.)
- Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
| | - Yonggoo Kim
- Catholic Genetic Laboratory Center, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (Y.H.); (J.-M.L.); (C.L.); (D.N.); (Y.K.)
- Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
| |
Collapse
|
|
3
|
Gadalla SM, Katki HA, Lai TP, Auer PL, Dagnall CL, Bupp C, Hutchinson AA, Anderson JJ, Mendez KJW, Spellman SR, Stewart V, Savage SA, Lee SJ, Levine JE, Saber W, Aviv A. Donor telomeres and their magnitude of shortening post-allogeneic haematopoietic cell transplant impact survival for patients with early-stage leukaemia or myelodysplastic syndrome. EBioMedicine 2025; 114:105641. [PMID: 40058159 PMCID: PMC11930427 DOI: 10.1016/j.ebiom.2025.105641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 02/05/2025] [Accepted: 02/25/2025] [Indexed: 03/28/2025] Open
Abstract
BACKGROUND Donor selection is a key success factor in allogeneic haematopoietic cell transplant (HCT). We evaluated the potential impact of donor leucocyte telomere length (LTL) and LTL shortening in recipients at three-month post-HCT (LTL-3MS) on the two-year HCT outcomes. METHODS We identified a cohort of 384 HCT recipients for early-stage leukaemia or myelodysplastic syndrome in the Blood and Marrow Transplant Clinical Trial Network protocol#1202 with blood samples collected three-month post-HCT. Blood samples from respective donors were available at the Centre for International Blood and Marrow Transplant Research biorepository. We used Cox proportional hazards models for statistical analyses. FINDINGS A better two-year overall survival (OS) was associated with longer donor LTL (adjusted-hazard ratio [HR] = 0.60, 95% confidence interval [CI] = 0.37-0.96, for LTL ≥6.7 kb vs LTL< 6.7 kb, p = 0.03), and higher LTL-3MS (HR = 0.52, 95% CI = 0.34-0.80, for LTL-3MS ≥ 230 vs < 230 bp, p = 0.003). Longer donor LTL was associated with a lower risk of non-relapse mortality (NRM; HR = 0.48, p = 0.05), while higher LTL-3MS was associated with lower relapse risk (HR for relapse risk = 0.53, p = 0.008). The adjusted 2-year cumulative risk of all-cause mortality was reduced by about half for patients with both donor LTL ≥6.7 kb and LTL-3MS ≥ 230 bp vs patients with neither characteristic (21% vs 41%, respectively; p < 0.0001). INTERPRETATION Selection of donors with longer LTL may improve HCT outcomes. Limited LTL shortening in recipients post-HCT may guide relapse prediction. FUNDING The NCI intramural research program and NIH grant U01AG066529.
Collapse
Affiliation(s)
- Shahinaz M Gadalla
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
| | - Hormuzd A Katki
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Tsung-Po Lai
- Center of Human Development and Aging, New Jersey Medical School, Rutgers, NJ, USA
| | - Paul L Auer
- Division of Biostatistics, Institute for Health and Equity, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Casey L Dagnall
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA; Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Rockville, MD, USA
| | - Caitrin Bupp
- Center for International Blood and Marrow Transplant Research, NMDP, Minneapolis, MN, USA
| | - Amy A Hutchinson
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA; Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Rockville, MD, USA
| | - James J Anderson
- College of the Environment, University of Washington, Seattle, WA, USA
| | - Kyra J W Mendez
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Stephen R Spellman
- Center for International Blood and Marrow Transplant Research, NMDP, Minneapolis, MN, USA
| | - Valerie Stewart
- Center for International Blood and Marrow Transplant Research, NMDP, Minneapolis, MN, USA
| | - Sharon A Savage
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Stephanie J Lee
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA; Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - John E Levine
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Wael Saber
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA; Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Abraham Aviv
- Center of Human Development and Aging, New Jersey Medical School, Rutgers, NJ, USA
| |
Collapse
|
|
4
|
Dratwa-Kuzmin M, Lacina P, Wysoczanska B, Kilinska D, Siemaszko J, Sobczyk-Kruszelnicka M, Fidyk W, Solarska I, Nasiłowska-Adamska B, Skowronska P, Bieniaszewska M, Tomaszewska A, Basak G, Giebel S, Bogunia-Kubik K. Telomere length and telomerase reverse transcriptase gene polymorphism as potential markers of complete chimerism and GvHD development after allogeneic haematopoietic stem cell transplantation. J Cancer Res Clin Oncol 2025; 151:109. [PMID: 40082305 PMCID: PMC11906511 DOI: 10.1007/s00432-025-06160-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Accepted: 03/05/2025] [Indexed: 03/16/2025]
Abstract
INTRODUCTION Telomerase reverse transcriptase (TERT) is a catalytic subunit of telomerase that maintains genome stability by maintaining telomere length (TL). The massive proliferation of donor cells in the recipient's body for engraftment results in accelerated telomere shortening. Genetic variability within the TERT gene affects telomerase activity, and was shown to influence of haematopoietic stem cell transplantation (HSCT) outcome. In the present study, we aimed to analyse the effect of recipient and donor TL and TERT single nucleotide polymorphism (SNP) on the occurrence of post-HSCT complications. METHODS Our study included 120 recipient-donor pairs. TERT promoter (TERTp) SNP (rs2853669) SNP variant was detected with the use of the LightSNiP typing assay employing real-time polymerase chain reaction (PCR) amplifications. Telomere length measurements were performed using qPCR test kits (ScienCell's Absolute Human Telomere Length Quantification qPCR Assay Kit [AHTLQ], Carlsbad, CA, USA). RESULTS The presence of TERTp rs2853669 T allele in the recipient was associated with a higher risk for acute graft-versus-host-disease (aGvHD) manifestation (p = 0.046) and a significantly shorter aGvHD-free survival (p = 0.041). The latter association was further confirmed in a Cox proportional hazards model (p = 0.043). However, no statistically significant association between telomere length and post-transplant complications was observed. Furthermore, we found that shorter TL characterized donors of patients with late complete chimerism at 180 day after HSCT (p = 0.011). CONCLUSION Our results suggest that recipient allele TERTp rs2853669 T is a marker of unfavourable outcome in the context of aGvHD. Shorter TL in donors could be associated with later achievement of complete chimerism.
Collapse
Affiliation(s)
- Marta Dratwa-Kuzmin
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.
| | - Piotr Lacina
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Barbara Wysoczanska
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Dorota Kilinska
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Jagoda Siemaszko
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Malgorzata Sobczyk-Kruszelnicka
- Department of Bone Marrow Transplantation and Hematology-Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland
| | - Wojciech Fidyk
- Department of Bone Marrow Transplantation and Hematology-Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland
| | - Iwona Solarska
- Institute of Hematology and Blood Transfusion Medicine, Warsaw, Poland
| | | | | | - Maria Bieniaszewska
- Department of Hematology and Transplantology, Medical University of Gdansk, Gdansk, Poland
| | - Agnieszka Tomaszewska
- Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Grzegorz Basak
- Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Sebastian Giebel
- Department of Bone Marrow Transplantation and Hematology-Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland
| | - Katarzyna Bogunia-Kubik
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.
| |
Collapse
|
|
5
|
El Jurdi N, Pavletic SZ. A contemporary downtrend in chronic GVHD? Blood Adv 2024; 8:5875-5877. [PMID: 39546299 DOI: 10.1182/bloodadvances.2024014586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2024] Open
Affiliation(s)
- Najla El Jurdi
- Immune Deficiency Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Steven Z Pavletic
- Immune Deficiency Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| |
Collapse
|
|
6
|
Mao H, Lin T, Huang S, Xie Z, Chen J, Shen X, Ding Y, Xu G, Chen Z. Association between monocyte to high-density lipoprotein cholesterol ratio and telomere length: based on NHANES 1999-2002. BMC Cardiovasc Disord 2024; 24:616. [PMID: 39497037 PMCID: PMC11533404 DOI: 10.1186/s12872-024-04301-3] [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: 06/19/2024] [Accepted: 10/25/2024] [Indexed: 11/06/2024] Open
Abstract
BACKGROUND Telomere length is closely associated with the occurrence and development of cardiovascular and other diseases. Monocyte to high-density lipoprotein cholesterol ratio (MHR) is a novel indicator of inflammation, oxidative stress, and metabolic syndrome, with some predictive ability for related disease risks in clinical practice. However, there is no research on the correlation between these two factors. METHODS Using data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002, we conducted analysis and research on the correlation between MHR and telomere length using the Kruskal-Wallis H test, Spearman rank correlation analysis, and partial correlation analysis. Weighted linear regression analysis assessed the strength of the association between the two variables, while restricted cubic spline regression (RCS) explored potential nonlinear relationships between them. RESULTS The results of correlation analysis showed that MHR levels were negatively correlated with telomere length (ρ=-0.083, P < 0.001), and this relationship remained statistically significant after controlling for other covariates (P all < 0.001). Weighted linear regression analysis showed that after adjusting for all covariates, MHR remained negatively associated with telomere length (β = -0.020; 95% CI: -0.039 to -0.002; P = 0.037). Subgroup analysis shows that the negative association between MHR and telomere length appeared more striking among females (𝛽 = -0.024; 95%CI: -0.050 to 0.001; P = 0.058), the Non-Hispanic White (𝛽 = -0.022; 95%CI: -0.045 to 0.002; P = 0.066), and other race (𝛽 = -0.067; 95%CI: -0.134 to -0.000; P = 0.049). Using RCS explored potential nonlinear relationships between MHR and telomere length, revealing no nonlinear relationship between the two (P = 0.102). CONCLUSIONS This study suggests a negative correlation between MHR levels and telomere length in American adults. More comprehensive research is needed to confirm these findings in the future.
Collapse
Affiliation(s)
- Haiyan Mao
- Department of Critical Care Medicine, Ningbo Medical Center Lihuili Hospital, Ningbo, 315100, China
| | - Tong Lin
- Department of Critical Care Medicine, Ningbo Medical Center Lihuili Hospital, Ningbo, 315100, China
| | - Shanshan Huang
- Department of Critical Care Medicine, Ningbo Medical Center Lihuili Hospital, Ningbo, 315100, China
| | - Zhenye Xie
- Department of Critical Care Medicine, Ningbo Medical Center Lihuili Hospital, Ningbo, 315100, China
| | - Jialu Chen
- Department of Critical Care Medicine, Ningbo Medical Center Lihuili Hospital, Ningbo, 315100, China
| | - Xingkai Shen
- Department of Critical Care Medicine, Ningbo Medical Center Lihuili Hospital, Ningbo, 315100, China
| | - Yi Ding
- Department of Critical Care Medicine, Ningbo Medical Center Lihuili Hospital, Ningbo, 315100, China
| | - Guangze Xu
- Department of Cardiovascular Medicine, Ningbo Medical Center Lihuili Hospital, Ningbo, 315100, China
| | - Zhikui Chen
- Department of Cardiovascular Medicine, Ningbo Medical Center Lihuili Hospital, Ningbo, 315100, China.
| |
Collapse
|
|
7
|
Milesi J, Gras D, Chanez P, Coiffard B. Airway epithelium in lung transplantation: a potential actor for post-transplant complications? Eur Respir Rev 2024; 33:240093. [PMID: 39603662 PMCID: PMC11600126 DOI: 10.1183/16000617.0093-2024] [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: 04/26/2024] [Accepted: 09/20/2024] [Indexed: 11/29/2024] Open
Abstract
Lung transplantation, a critical intervention for end-stage lung diseases, is frequently challenged by post-transplant complications. Indeed, primary graft dysfunction, anastomotic complications, infections and acute and chronic rejections pose significant hurdles in lung transplantation. While evidence regarding the role of airway epithelium after lung transplantation is still emerging, its importance is becoming increasingly recognised. This review looks at the complex involvement of airway epithelium in various post-transplant complications, while emphasising the utility of airway epithelial culture as a research model. In summary, by elucidating the involvement of airway epithelium in each post-transplant complication and explaining these intricate processes, the review aims to guide specific future research efforts and therapeutic strategies aimed at improving lung transplant outcomes and enhancing patient care.
Collapse
Affiliation(s)
- Jules Milesi
- Aix-Marseille University, APHM, Department of Respiratory Medicine and Lung Transplantation, Marseille, France
- Aix-Marseille University, INSERM, INRAE, C2VN, Marseille, France
| | - Delphine Gras
- Aix-Marseille University, INSERM, INRAE, C2VN, Marseille, France
| | - Pascal Chanez
- Aix-Marseille University, APHM, Department of Respiratory Medicine and Lung Transplantation, Marseille, France
- Aix-Marseille University, INSERM, INRAE, C2VN, Marseille, France
| | - Benjamin Coiffard
- Aix-Marseille University, APHM, Department of Respiratory Medicine and Lung Transplantation, Marseille, France
- Aix-Marseille University, INSERM, INRAE, C2VN, Marseille, France
| |
Collapse
|
|
8
|
Yun Z, Liu Z, Shen Y, Sun Z, Zhao H, Du X, Lv L, Zhang Y, Hou L. Genetic analysis from multiple cohorts implies causality between 2200 druggable genes, telomere length, and leukemia. Comput Biol Med 2024; 181:109064. [PMID: 39216403 DOI: 10.1016/j.compbiomed.2024.109064] [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: 04/22/2024] [Revised: 08/14/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Clinical therapeutic targets for leukemia remain to be identified and the causality between leukemia and telomere length is unclear. METHODS This work employed cis expression quantitative trait locus (eQTL) for 2,200 druggable genes from the eQTLGen Consortium and genome-wide association studies (GWAS) summary data for telomere length in seven blood cell types from the UK Biobank, Netherlands Cohort as exposures. GWAS data for lymphoid leukemia (LL) and myeloid leukemia (ML) from FinnGen and Lee Lab were used as outcomes for discovery and replication cohorts, respectively. Robust Mendelian randomization (MR) findings were generated from seven MR models and a series of sensitivity analyses. Summary-data-based MR (SMR) analysis and transcriptome-wide association studies (TWAS) were further implemented to verify the association between identified druggable genes and leukemia. Single-cell type expression analysis was employed to identify the specific expression of leukemia casual genes on human bone marrow and peripheral blood immune cells. Multivariable MR analysis, linkage disequilibrium score regression (LDSC), and Bayesian colocalization analysis were performed to further validate the relationship between telomere length and leukemia. Mediation analysis was used to assess the effects of identified druggable genes affecting leukemia via telomere length. Phenome-wide MR (Phe-MR) analysis for assessing the effect of leukemia causal genes and telomere length on 1,403 disease phenotypes. RESULTS Combining the results of the meta-analysis for MR estimates from two cohorts, SMR and TWAS analysis, we identified five LL causal genes (TYMP, DSTYK, PPIF, GDF15, FAM20A) and three ML causal genes (LY75, ADA, ABCA2) as promising drug targets for leukemia. Univariable MR analysis showed genetically predicted higher leukocyte telomere length increased the risk of LL (odds ratio [OR] = 2.33, 95 % confidence interval [95 % CI] 1.70-3.18; P = 1.33E-07), and there was no heterogeneity and horizontal pleiotropy. Evidence from the meta-analysis of two cohorts strengthened this finding (OR = 1.88, 95 % CI 1.06-3.05; P = 0.01). Multivariable MR analysis showed the causality between leukocyte telomere length and LL without interference from the other six blood cell telomere length (OR = 2.72, 95 % CI 1.88-3.93; P = 1.23E-07). Evidence from LDSC supported the positive genetic correlation between leukocyte telomere length and LL (rg = 0.309, P = 0.0001). Colocalization analysis revealed that the causality from leukocyte telomere length on LL was driven by the genetic variant rs770526 in the TERT region. The mediation analysis via two-step MR showed that the causal effect from TYMP on LL was partly mediated by leukocyte telomere length, with a mediated proportion of 12 %. CONCLUSION Our study identified several druggable genes associated with leukemia risk and provided new insights into the etiology and drug development of leukemia. We also found that genetically predicted higher leukocyte telomere length increased LL risk and its potential mechanism of action.
Collapse
Affiliation(s)
- Zhangjun Yun
- Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China; Graduate School of Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Zhu Liu
- Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China; Graduate School of Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Yang Shen
- Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Ziyi Sun
- Graduate School of Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Hongbin Zhao
- Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China; Graduate School of Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Xiaofeng Du
- Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China; Graduate School of Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Liyuan Lv
- Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China.
| | - Yayue Zhang
- Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China.
| | - Li Hou
- Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China.
| |
Collapse
|
|
9
|
Rafati M, McReynolds LJ, Wang Y, Hicks B, Jones K, Spellman SR, He M, Bolon YT, Arrieta-Bolaños E, Saultz JN, Lee SJ, Savage SA, Gadalla SM. Hemophagocytic Lymphohistiocytosis Gene Variants in Severe Aplastic Anemia and Their Impact on Hematopoietic Cell Transplantation Outcomes. Transplant Cell Ther 2024; 30:770.e1-770.e10. [PMID: 38810947 PMCID: PMC11296907 DOI: 10.1016/j.jtct.2024.05.017] [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: 03/24/2024] [Revised: 05/20/2024] [Accepted: 05/23/2024] [Indexed: 05/31/2024]
Abstract
Germline genetic testing for patients with severe aplastic anemia (SAA) is recommended to guide treatment, including the use of immunosuppressive therapy and/or adjustment of hematopoietic cell transplantation (HCT) modalities. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory condition often associated with cytopenias with autosomal recessive (AR) or X-linked recessive (XLR) inheritance. HLH is part of the SAA differential diagnosis, and genetic testing may identify variants in HLH genes in patients with SAA. The impact of pathogenic/likely pathogenic (P/LP) variants in HLH genes on HCT outcomes in SAA is unclear. In this study, we aimed to determine the frequency of HLH gene variants in a large cohort of patients with acquired SAA and to evaluate their association(s) with HCT outcomes. The Transplant Outcomes in Aplastic Anemia project, a collaboration between the National Cancer Institute and the Center for International Blood and Marrow Transplant Research, collected genomic and clinical data from 824 patients who underwent HCT for SAA between 1989 and 2015. We excluded 140 patients with inherited bone marrow failure syndromes and used exome sequencing data from the remaining 684 patients with acquired SAA to identify P/LP variants in 14 HLH-associated genes (11 AR, 3 XLR) curated using American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) criteria. Deleterious variants of uncertain significance (del-VUS) were defined as those not meeting the ACMG/AMP P/LP criteria but with damaging predictions in ≥3 of 5 meta-predictors (BayesDel, REVEL, CADD, MetaSVM, and/or EIGEN). The Kaplan-Meier estimator was used to calculate the probability of overall survival (OS) after HCT, and the cumulative incidence calculator was used for other HCT outcomes, accounting for relevant competing risks. There were 46 HLH variants in 49 of the 684 patients (7.2%). Seventeen variants in 19 patients (2.8%) were P/LP; 8 of these were loss-of-function variants. Among the 19 patients with P/LP HLH variants, 16 (84%) had monoallelic variants in genes with AR inheritance, and 3 had variants in XLR genes. PRF1 was the most frequently affected gene (in 8 of the 19 patients). We found no statistically significant differences in transplantation-related factors between patients with and those without P/LP HLH variants. The 5-year survival probability was 89% (95% confidence interval [CI], 72% to 99%) in patients with P/LP HLH variants and 70% (95% CI, 53% to 85%) in those with del-VUS HLH variants, compared to 66% (95% CI, 62% to 70%) in those without variants (P = .16, log-rank test). The median time to neutrophil engraftment was 16 days for patients with P/LP HLH variants and 18 days in those with del-VUS HLH variants or without variants combined (P = .01, Gray's test). No statistically significant associations between P/LP HLH variants and the risk of acute or chronic graft-versus-host disease were noted. In this large cohort of patients with acquired SAA, we found that 2.8% of patients harbored a P/LP variant in an HLH gene. No negative effects of HLH gene variants on post-HCT survival were noted. The small number of patients with P/LP HLH variants limits the study's ability to provide conclusive evidence; nonetheless, our data suggest that there is no need for special transplantation considerations for patients with SAA carrying P/LP variants.
Collapse
Affiliation(s)
- Maryam Rafati
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
| | - Lisa J McReynolds
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Youjin Wang
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Belynda Hicks
- Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland; Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Kristine Jones
- Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland; Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Stephen R Spellman
- Center for International Blood and Marrow Transplant Research, National Marrow Donor Program, Minneapolis, Minnesota
| | - Meilun He
- Center for International Blood and Marrow Transplant Research, National Marrow Donor Program, Minneapolis, Minnesota
| | - Yung-Tsi Bolon
- Center for International Blood and Marrow Transplant Research, National Marrow Donor Program, Minneapolis, Minnesota
| | - Esteban Arrieta-Bolaños
- Institute for Experimental Cellular Therapy, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Heidelberg, Germany
| | - Jennifer N Saultz
- Division of Hematology/Medical Oncology, Oregon Health & Science University, Portland, Oregon
| | - Stephanie J Lee
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin; Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Sharon A Savage
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Shahinaz M Gadalla
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| |
Collapse
|
|
10
|
Ng GYQ, Hande MP. Use of peptide nucleic acid probe to determine telomere dynamics in improving chromosome analysis in genetic toxicology studies. MUTATION RESEARCH. GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2024; 897:503773. [PMID: 39054004 DOI: 10.1016/j.mrgentox.2024.503773] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 05/01/2024] [Accepted: 05/22/2024] [Indexed: 07/27/2024]
Abstract
Genetic toxicology, strategically located at the intersection of genetics and toxicology, aims to demystify the complex interplay between exogenous agents and our genetic blueprint. Telomeres, the protective termini of chromosomes, play instrumental roles in cellular longevity and genetic stability. Traditionally karyotyping and fluorescence in situ hybridisation (FISH), have been indispensable tools for chromosomal analysis following exposure to genotoxic agents. However, their scope in discerning nuanced molecular dynamics is limited. Peptide Nucleic Acids (PNAs) are synthetic entities that embody characteristics of both proteins and nucleic acids and have emerged as potential game-changers. This perspective report comprehensively examines the vast potential of PNAs in genetic toxicology, with a specific emphasis on telomere research. PNAs' superior resolution and precision make them a favourable choice for genetic toxicological assessments. The integration of PNAs in contemporary analytical workflows heralds a promising evolution in genetic toxicology, potentially revolutionizing diagnostics, prognostics, and therapeutic avenues. In this timely review, we attempted to assess the limitations of current PNA-FISH methodology and recommend refinements.
Collapse
Affiliation(s)
- Gavin Yong Quan Ng
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Manoor Prakash Hande
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
| |
Collapse
|
|
11
|
Yang SH, Liu HT, Wang TF, Liou YS, Sun DS, Wang JH, Chen LY. Shorter donor leukocyte telomere length is associated with poor peripheral blood stem cell mobilization induced by granulocyte colony-stimulating factor. J Formos Med Assoc 2024:S0929-6646(24)00294-8. [PMID: 38914514 DOI: 10.1016/j.jfma.2024.06.017] [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: 03/17/2024] [Revised: 06/16/2024] [Accepted: 06/18/2024] [Indexed: 06/26/2024] Open
Abstract
BACKGROUND/PURPOSE Insufficient numbers of peripheral blood stem cells (PBSC) after granulocyte colony-stimulating factor (G-CSF) mobilization occurs in a significant proportion of PBSC collections, often from older age donors. Telomere length (TL) is often used as an indicator of an individual's biological age. This study aimed to investigate the relationship between donors' leukocyte TL and the outcome of G-CSF-induced PBSC mobilization in healthy unrelated donors. METHODS Donors' leukocyte TLs and the outcome of G-CSF-induced PBSC mobilization, as assessed by pre-harvest CD34+ cell counts, were analyzed in 39 healthy PBSC donors. TL in a non-mobilized general population (n = 90) was included as a control group. G-CSF mobilization effect was categorized into three groups according to pre-harvest CD34+ cell count: poor (≤25/μL, PMD), intermediate (between 25 and 180/μL), and good (≥180/μl, GMD). RESULTS Leukocyte TL of PBSC donors correlated well with pre-harvest CD34+ cell counts (r = 0.645, p < 0.001). Leukocyte TLs of PMDs (n = 8) were significantly shorter than those of GMDs (n = 9) and non-mobilization controls (p < 0.05). Moreover, all PMD TLs were below the 50th percentile, and 62.5% of PMDs had TLs below the 10th percentile of age-matched control participants. In contrast, no GMD TLs were below the 10th percentile; in fact, 33.3% (3/9) of them were above the 90th percentile. CONCLUSION Our results indicate that shorter donor leukocyte TL is associated with poor G-CSF-induced PBSC mobilization. TL, which represents a donor's biological age, could be a potential predictor for mobilization outcome.
Collapse
Affiliation(s)
- Shang-Hsien Yang
- Department of Pediatric Hematology and Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan; Department of Medicine, College of Medicine, Tzu Chi University, Hualien, Taiwan; Stem Cells Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
| | - Hsin-Tzu Liu
- Department of Medicine Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Tso-Fu Wang
- Department of Medicine, College of Medicine, Tzu Chi University, Hualien, Taiwan; Department of Hematology and Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan; Stem Cells Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Yu-Shan Liou
- Department of Molecular Biology and Human Genetics, College of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Der-Shan Sun
- Department of Molecular Biology and Human Genetics, College of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Jen-Hong Wang
- Department of Medicine Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Liuh-Yow Chen
- Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
| |
Collapse
|
|
12
|
Munshi PN, McCurdy SR. Age barriers in allogeneic hematopoietic cell transplantation: Raising the silver curtain. Am J Hematol 2024; 99:922-937. [PMID: 38414188 DOI: 10.1002/ajh.27228] [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: 07/14/2023] [Revised: 12/13/2023] [Accepted: 01/01/2024] [Indexed: 02/29/2024]
Abstract
Allogeneic hematopoietic cell transplantation (HCT) is no longer exclusively for the young. With an aging population, development of non-intensive remission-inducing strategies for hematologic malignancies, and novel graft-versus-host disease-prevention platforms, an older population of patients is pursuing HCT. The evolving population of HCT recipients requires an overhaul in the way we risk-stratify and optimize patients prior to HCT. Here, we review the history and current state of HCT for older adults and propose an assessment and intervention flow to bridge the gaps in today's clinical guidelines.
Collapse
Affiliation(s)
- Pashna N Munshi
- Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Shannon R McCurdy
- Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| |
Collapse
|
|
13
|
Barade A, Lakshmi KM, Korula A, Abubacker FN, Kulkarni UP, Abraham A, Mathews V, George B, Edison ES. Comparison of telomere length in patients with bone marrow failure syndromes and healthy controls. Eur J Haematol 2024; 112:810-818. [PMID: 38213291 DOI: 10.1111/ejh.14173] [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: 09/21/2023] [Revised: 01/02/2024] [Accepted: 01/03/2024] [Indexed: 01/13/2024]
Abstract
INTRODUCTION During normal aging, telomeric DNA is gradually lost in dividing somatic cells, and critically short telomeres lead to replicative senescence, apoptosis, or chromosomal instability. We studied telomere length in bone marrow failure syndromes (BMFS) compared to normal healthy population. METHODS Peripheral blood was collected from the participants, and genomic DNA was extracted. Relative telomere length was measured using a quantitative polymerase chain reaction. Statistical analysis was performed using SPSS and GraphPad Prism 8.2 software. RESULTS The median age of normal Indian population was 31 (0-60) years. As expected, telomere length (TL) showed a decline with age and no difference in TL between males and females. The median age of 650 patients with aplastic anemia (AA) was 30 (1-60) years. TL was significantly shorter in patients with AA compared to healthy controls (p < .001). In FA and MDS patients, TL was significantly shorter than age-matched healthy controls (p = .028; p < .001), respectively. There was no difference between the median TL in age-matched AA and FA patients (p = .727). However, patients with MDS had shorter TL than age-matched AA (p = .031). CONCLUSION TL in BMF syndrome patients was significantly shorter than age-matched healthy controls.
Collapse
Affiliation(s)
- Aruna Barade
- Department of Haematology, Christian Medical College, Vellore, India
- Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, India
| | - Kavitha M Lakshmi
- Department of Haematology, Christian Medical College, Vellore, India
| | - Anu Korula
- Department of Haematology, Christian Medical College, Vellore, India
| | | | - Uday P Kulkarni
- Department of Haematology, Christian Medical College, Vellore, India
| | - Aby Abraham
- Department of Haematology, Christian Medical College, Vellore, India
| | - Vikram Mathews
- Department of Haematology, Christian Medical College, Vellore, India
| | - Biju George
- Department of Haematology, Christian Medical College, Vellore, India
| | - Eunice S Edison
- Department of Haematology, Christian Medical College, Vellore, India
| |
Collapse
|
|
14
|
Wang Y, Liu Q, Liang S, Yao M, Zheng H, Hu D, Wang Y. Genetically predicted telomere length and the risk of 11 hematological diseases: a Mendelian randomization study. Aging (Albany NY) 2024; 16:4270-4281. [PMID: 38393686 PMCID: PMC10968687 DOI: 10.18632/aging.205583] [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: 10/13/2023] [Accepted: 01/24/2024] [Indexed: 02/25/2024]
Abstract
OBJECTIVE Previous studies have demonstrated that various hematologic diseases (HDs) induce alterations in telomere length (TL). The aim of this study is to investigate whether genetically predicted changes in TL have an impact on the risk of developing HDs. METHODS GWAS data for TL and 11 HDs were extracted from the database. The R software package "TwoSampleMR" was employed to conduct a two-sample Mendelian randomization (MR) analysis, in order to estimate the influence of TL changes on the risk of developing the 11 HDs. RESULTS We examined the effect of TL changes on the risk of developing the 11 HDs. The IVW results revealed a significant causal association between genetically predicted longer TL and the risk of developing acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MANTLE), and hodgkin lymphoma (HODGKIN). However, there was no significant causal relationship observed between TL changes and the risk of developing chronic myeloid leukemia (CML), diffuse large b-cell lymphoma (DLBCL), marginal zone b-cell lymphoma (MARGINAL), follicular lymphoma (FOLLICULAR), monocytic leukemia (MONOCYTIC), and mature T/NK-cell lymphomas (TNK). CONCLUSIONS The MR analysis revealed a positive association between genetically predicted longer TL and an increased risk of developing ALL, AML, CLL, MANTLE, and HODGKIN. This study further supports the notion that cells with longer TL have greater proliferative and mutational potential, leading to an increased risk of certain HDs.
Collapse
Affiliation(s)
- Yimin Wang
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Qi Liu
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shibing Liang
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Minghao Yao
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Huimin Zheng
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Dongqing Hu
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yifei Wang
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| |
Collapse
|
|
15
|
Saliba RM, Kanakry CG, Gadalla S, Kebriaei P, Rezvani K, Champlin RE, Shpall EJ, Weisdorf D, Mehta RS. Effect of donor age in patients with acute myeloid leukemia undergoing haploidentical hematopoietic cell transplantation vary by conditioning intensity and recipient age. Am J Hematol 2024; 99:38-47. [PMID: 37850688 DOI: 10.1002/ajh.27126] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 09/04/2023] [Accepted: 09/27/2023] [Indexed: 10/19/2023]
Abstract
We investigated the impact of donor age (younger [≤35 years] vs. older [>35 years]) after accounting for other non-HLA and HLA factors on outcomes of patients with acute myeloid leukemia undergoing HLA-haploidentical hematopoietic cell transplantation (n = 790). The effect differed by conditioning-partly related to the differences in the recipient age in myeloablative (MAC; median 46 years) versus reduced-intensity/non-myeloablative conditioning (RIC/NMA; median 61 years) groups. With MAC (n = 320), donor age had no impact on acute graft-versus-host disease (GVHD), but older donors were associated with a significantly higher risk of chronic GVHD (hazard ratio [HR]: 1.6, 95% confidence interval [CI]: 1.10-2.30, p = .02) independent of recipient age and other factors. Donor age had no impact on either relapse or non-relapse mortality (NRM). The impact of donor/recipient age on overall survival changed over time. Older donors were associated with significantly higher late overall mortality (>6 months) in younger recipients (≤ 50 years; HR: 2.2, 95% CI: 1.03-4.6, p = .04) but not older recipients. With RIC/NMA (n = 470), neither recipient's nor donor's age influenced the risk of GVHD. Donor age had no significant impact on the risk of relapse, but older donors were associated with a significantly higher risk of NRM (HR: 1.6, 95% CI: 1.02-2.6, p = .04) independent of recipient age. Older donor age was associated with significantly higher late overall mortality (>9 months) in older recipients (>50 years; HR: 1.66, 95% CI: 1.0-2.67; p = .049) but not in younger recipients. Donor selection based on donor age may require a tailored approach for a particular recipient.
Collapse
Affiliation(s)
- Rima M Saliba
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Christopher G Kanakry
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Shahinaz Gadalla
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Partow Kebriaei
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Katayoun Rezvani
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Richard E Champlin
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Elizabeth J Shpall
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Daniel Weisdorf
- Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Rohtesh S Mehta
- Clinical Research Division, Adult Blood and Marrow Transplantation, Fred Hutchison Cancer Center, Seattle, Washington, USA
| |
Collapse
|
|
16
|
Mushtaq AH, Shafqat A, Salah HT, Hashmi SK, Muhsen IN. Machine learning applications and challenges in graft-versus-host disease: a scoping review. Curr Opin Oncol 2023; 35:594-600. [PMID: 37820094 DOI: 10.1097/cco.0000000000000996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/13/2023]
Abstract
PURPOSE OF REVIEW This review delves into the potential of artificial intelligence (AI), particularly machine learning (ML), in enhancing graft-versus-host disease (GVHD) risk assessment, diagnosis, and personalized treatment. RECENT FINDINGS Recent studies have demonstrated the superiority of ML algorithms over traditional multivariate statistical models in donor selection for allogeneic hematopoietic stem cell transplantation. ML has recently enabled dynamic risk assessment by modeling time-series data, an upgrade from the static, "snapshot" assessment of patients that conventional statistical models and older ML algorithms offer. Regarding diagnosis, a deep learning model, a subset of ML, can accurately identify skin segments affected with chronic GVHD with satisfactory results. ML methods such as Q-learning and deep reinforcement learning have been utilized to develop adaptive treatment strategies (ATS) for the personalized prevention and treatment of acute and chronic GVHD. SUMMARY To capitalize on these promising advancements, there is a need for large-scale, multicenter collaborations to develop generalizable ML models. Furthermore, addressing pertinent issues such as the implementation of stringent ethical guidelines is crucial before the widespread introduction of AI into GVHD care.
Collapse
Affiliation(s)
- Ali Hassan Mushtaq
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Areez Shafqat
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Haneen T Salah
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas
| | - Shahrukh K Hashmi
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
- Department of Medicine, Sheikh Shakbout Medical City
- Medical Affairs, Khalifa University, Abu Dhabi, United Arab Emirates
| | - Ibrahim N Muhsen
- Section of Hematology and Oncology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| |
Collapse
|
|
17
|
Yan J, Jin T, Wang L. Hematopoietic stem cell transplantation of aplastic anemia by relative with mutations and normal telomere length: A case report. World J Clin Cases 2023; 11:7200-7206. [PMID: 37946752 PMCID: PMC10631418 DOI: 10.12998/wjcc.v11.i29.7200] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 09/09/2023] [Accepted: 09/26/2023] [Indexed: 10/13/2023] Open
Abstract
BACKGROUND Immunosuppressive therapy and matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) are the preferred treatments for aplastic anemia (AA). CASE SUMMARY In this report, we describe a 43-year-old male patient with severe AA who carried BRIP1 (also known as FANCJ), TINF2, and TCIRG1 mutations. Screening of the family pedigree revealed the same TINF2 mutation in his mother and older brother, with his older brother also carrying the BRIP1 variant and demonstrating normal telomere length and hematopoietic function. The patient was successfully treated with oral cyclosporine A, eltrombopag, and acetylcysteine, achieving remission 4 years after receiving MSD-HSCT from his older brother. CONCLUSION This case provides a valuable clinical reference for individuals with suspected pathogenic gene mutations, normal telomere length, and hematopoietic function, highlighting them as potential donors for patients with AA.
Collapse
Affiliation(s)
- Jin Yan
- School of Medicine, Jianghan University, Wuhan 430056, Hubei Province, China
- Department of Hematology, The Central Hospital of Wuhan, Wuhan 430014, Hubei Province, China
| | - Ting Jin
- Department of Hematology, The Central Hospital of Wuhan, Wuhan 430014, Hubei Province, China
| | - Li Wang
- Department of Hematology, The Central Hospital of Wuhan, Wuhan 430014, Hubei Province, China
| |
Collapse
|
|
18
|
Aplastic Anemia as a Roadmap for Bone Marrow Failure: An Overview and a Clinical Workflow. Int J Mol Sci 2022; 23:ijms231911765. [PMID: 36233062 PMCID: PMC9569739 DOI: 10.3390/ijms231911765] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 09/27/2022] [Accepted: 09/28/2022] [Indexed: 11/27/2022] Open
Abstract
In recent years, it has become increasingly apparent that bone marrow (BM) failures and myeloid malignancy predisposition syndromes are characterized by a wide phenotypic spectrum and that these diseases must be considered in the differential diagnosis of children and adults with unexplained hematopoiesis defects. Clinically, hypocellular BM failure still represents a challenge in pathobiology-guided treatment. There are three fundamental topics that emerged from our review of the existing data. An exogenous stressor, an immune defect, and a constitutional genetic defect fuel a vicious cycle of hematopoietic stem cells, immune niches, and stroma compartments. A wide phenotypic spectrum exists for inherited and acquired BM failures and predispositions to myeloid malignancies. In order to effectively manage patients, it is crucial to establish the right diagnosis. New theragnostic windows can be revealed by exploring BM failure pathomechanisms.
Collapse
|
|
19
|
Lai TP, Verhulst S, Dagnall CL, Hutchinson A, Spellman SR, Howard A, Katki HA, Levine JE, Saber W, Aviv A, Gadalla SM. Decoupling blood telomere length from age in recipients of allogeneic hematopoietic cell transplant in the BMT-CTN 1202. Front Immunol 2022; 13:966301. [PMID: 36263045 PMCID: PMC9574912 DOI: 10.3389/fimmu.2022.966301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 08/26/2022] [Indexed: 11/13/2022] Open
Abstract
The age of allogeneic hematopoietic cell transplant (HCT) donors and their hematopoietic cell telomere length (TL) might affect recipients’ outcomes. Our goals were to examine the possible effect of these donors’ factors on the recipients’ hematopoietic cell TL and quantify hematopoietic cell TL shortening in the critical first three-month post-HCT. We measured hematopoietic cell TL parameters in 75 recipient-donor pairs, from the Blood and Marrow Transplant Clinical Trials Network (protocol#1202), by Southern blotting (SB), the Telomeres Shortest Length Assay (TeSLA), and quantitative PCR (qPCR). Recipients’ hematopoietic cell TL parameters post-HCT correlated with donors’ age (p<0.001 for all methods), but not recipients’ own age, and with donors’ pre-HCT hematopoietic cell TL (p<0.0001 for all). Multivariate analyses showed that donors’ hematopoietic cell TL pre-HCT, independent of donors’ age, explained most of the variability in recipients’ hematopoietic cell TL post-HCT (81% for SB, 56% for TeSLA, and 65% for qPCR; p>0.0001 for all). SB and TeSLA detected hematopoietic cell TL shortening in all recipients post-HCT (mean=0.52kb and 0.47kb, respectively; >15-fold the annual TL shortening in adults; p<0.00001 for both), but qPCR detected shortening only in 57.5% of recipients. TeSLA detected a buildup of post-HCT of telomeres <3 kb in 96% of recipients (p<0.0001). In conclusion, HCT decouples hematopoietic cell TL in the recipients from their own age to reflect the donors’ age. The potential donors’ age effect on outcomes of HCT might be partially mediated by short hematopoietic cell TL in older donors. qPCR-based TL measurement is suboptimal for detecting telomere shortening post-HCT.
Collapse
Affiliation(s)
- Tsung-Po Lai
- Center of Human Development and Aging, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United States
| | - Simon Verhulst
- Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, Netherlands
| | - Casey L. Dagnall
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States
- Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Amy Hutchinson
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States
- Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Stephen R. Spellman
- Center for International Blood and Marrow Transplant Research, National Marrow Donor Program, Minneapolis, MN, United States
| | - Alan Howard
- Center for International Blood and Marrow Transplant Research, National Marrow Donor Program, Minneapolis, MN, United States
| | - Hormuzd A. Katki
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States
| | - John E. Levine
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Wael Saber
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Abraham Aviv
- Center of Human Development and Aging, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United States
| | - Shahinaz M. Gadalla
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States
- *Correspondence: Shahinaz M. Gadalla,
| |
Collapse
|
|
20
|
McReynolds LJ, Rafati M, Wang Y, Ballew BJ, Kim J, Williams VV, Zhou W, Hendricks RM, Dagnall C, Freedman ND, Carter B, Strollo S, Hicks B, Zhu B, Jones K, Paczesny S, Marsh SGE, Spellman SR, He M, Wang T, Lee SJ, Savage SA, Gadalla SM. Genetic testing in severe aplastic anemia is required for optimal hematopoietic cell transplant outcomes. Blood 2022; 140:909-921. [PMID: 35776903 PMCID: PMC9412004 DOI: 10.1182/blood.2022016508] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 06/17/2022] [Indexed: 11/20/2022] Open
Abstract
Patients with severe aplastic anemia (SAA) can have an unrecognized inherited bone marrow failure syndrome (IBMFS) because of phenotypic heterogeneity. We curated germline genetic variants in 104 IBMFS-associated genes from exome sequencing performed on 732 patients who underwent hematopoietic cell transplant (HCT) between 1989 and 2015 for acquired SAA. Patients with pathogenic or likely pathogenic (P/LP) variants fitting known disease zygosity patterns were deemed unrecognized IBMFS. Carriers were defined as patients with a single P/LP variant in an autosomal recessive gene or females with an X-linked recessive P/LP variant. Cox proportional hazard models were used for survival analysis with follow-up until 2017. We identified 113 P/LP single-nucleotide variants or small insertions/deletions and 10 copy number variants across 42 genes in 121 patients. Ninety-one patients had 105 in silico predicted deleterious variants of uncertain significance (dVUS). Forty-eight patients (6.6%) had an unrecognized IBMFS (33% adults), and 73 (10%) were carriers. No survival difference between dVUS and acquired SAA was noted. Compared with acquired SAA (no P/LP variants), patients with unrecognized IBMFS, but not carriers, had worse survival after HCT (IBMFS hazard ratio [HR], 2.13; 95% confidence interval[CI], 1.40-3.24; P = .0004; carriers HR, 0.96; 95% CI, 0.62-1.50; P = .86). Results were similar in analyses restricted to patients receiving reduced-intensity conditioning (n = 448; HR IBMFS = 2.39; P = .01). The excess mortality risk in unrecognized IBMFS attributed to death from organ failure (HR = 4.88; P < .0001). Genetic testing should be part of the diagnostic evaluation for all patients with SAA to tailor therapeutic regimens. Carriers of a pathogenic variant in an IBMFS gene can follow HCT regimens for acquired SAA.
Collapse
Affiliation(s)
| | | | | | - Bari J Ballew
- Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
- Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD
| | | | | | - Weiyin Zhou
- Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
- Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD
| | | | - Casey Dagnall
- Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
- Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Neal D Freedman
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Brian Carter
- Department of Population Science, American Cancer Society, Atlanta, GA
| | - Sara Strollo
- Department of Population Science, American Cancer Society, Atlanta, GA
| | - Belynda Hicks
- Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
- Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Bin Zhu
- Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
- Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Kristine Jones
- Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
- Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Sophie Paczesny
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC
| | - Steven G E Marsh
- Anthony Nolan Research Institute and University College London Cancer Institute, London, United Kingdom
| | - Stephen R Spellman
- Center for International Blood and Marrow Transplant Research, National Marrow Donor Program, Minneapolis, MN
| | - Meilun He
- Center for International Blood and Marrow Transplant Research, National Marrow Donor Program, Minneapolis, MN
| | - Tao Wang
- Center for International Blood and Marrow Transplant Research and
- Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI; and
| | - Stephanie J Lee
- Center for International Blood and Marrow Transplant Research and
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | | | | |
Collapse
|
|
21
|
Silva TD, Voisey J, Hopkins P, Apte S, Chambers D, O'Sullivan B. Markers of rejection of a lung allograft: state of the art. Biomark Med 2022; 16:483-498. [PMID: 35315284 DOI: 10.2217/bmm-2021-1013] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Chronic lung allograft dysfunction (CLAD) affects approximately 50% of all lung transplant recipients by 5 post-operative years and is the leading cause of death in lung transplant recipients. Early CLAD diagnosis or ideally prediction of CLAD is essential to enable early intervention before significant lung injury occurs. New technologies have emerged to facilitate biomarker discovery, including epigenetic modification and single-cell RNA sequencing. This review examines new and existing technologies for biomarker discovery and the current state of research on biomarkers for identifying lung transplant rejection.
Collapse
Affiliation(s)
- Tharushi de Silva
- School of Biomedical Sciences, Centre for Genomics & Personalised Heath, Faculty of Health, Queensland University of Technology (QUT), Brisbane, Queensland, Australia.,Queensland Lung Transplant Service, Ground Floor, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Chermside, 4032, Brisbane, Queensland, Australia
| | - Joanne Voisey
- School of Biomedical Sciences, Centre for Genomics & Personalised Heath, Faculty of Health, Queensland University of Technology (QUT), Brisbane, Queensland, Australia
| | - Peter Hopkins
- Queensland Lung Transplant Service, Ground Floor, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Chermside, 4032, Brisbane, Queensland, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, The University of Queensland, 4032, Brisbane, Queensland, Australia
| | - Simon Apte
- Queensland Lung Transplant Service, Ground Floor, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Chermside, 4032, Brisbane, Queensland, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, The University of Queensland, 4032, Brisbane, Queensland, Australia
| | - Daniel Chambers
- School of Biomedical Sciences, Centre for Genomics & Personalised Heath, Faculty of Health, Queensland University of Technology (QUT), Brisbane, Queensland, Australia.,Queensland Lung Transplant Service, Ground Floor, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Chermside, 4032, Brisbane, Queensland, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, The University of Queensland, 4032, Brisbane, Queensland, Australia
| | - Brendan O'Sullivan
- School of Biomedical Sciences, Centre for Genomics & Personalised Heath, Faculty of Health, Queensland University of Technology (QUT), Brisbane, Queensland, Australia.,Queensland Lung Transplant Service, Ground Floor, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Chermside, 4032, Brisbane, Queensland, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, The University of Queensland, 4032, Brisbane, Queensland, Australia
| |
Collapse
|
|
22
|
Rossiello F, Jurk D, Passos JF, d'Adda di Fagagna F. Telomere dysfunction in ageing and age-related diseases. Nat Cell Biol 2022; 24:135-147. [PMID: 35165420 PMCID: PMC8985209 DOI: 10.1038/s41556-022-00842-x] [Citation(s) in RCA: 358] [Impact Index Per Article: 119.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 01/06/2022] [Indexed: 12/11/2022]
Abstract
Ageing organisms accumulate senescent cells that are thought to contribute to body dysfunction. Telomere shortening and damage are recognized causes of cellular senescence and ageing. Several human conditions associated with normal ageing are precipitated by accelerated telomere dysfunction. Here, we systematize a large body of evidence and propose a coherent perspective to recognize the broad contribution of telomeric dysfunction to human pathologies.
Collapse
Affiliation(s)
- Francesca Rossiello
- IFOM Foundation-FIRC Institute of Molecular Oncology Foundation, Milan, Italy
| | - Diana Jurk
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| | - João F Passos
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
| | - Fabrizio d'Adda di Fagagna
- IFOM Foundation-FIRC Institute of Molecular Oncology Foundation, Milan, Italy.
- Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (IGM-CNR), Pavia, Italy.
| |
Collapse
|
|
23
|
Barade A, Aboobacker F, Korula A, Lakshmi K, Devasia A, Abraham A, Mathews V, Edison E, George B. Impact of donor telomere length on survival in patients undergoing matched sibling donor transplantation for aplastic anaemia. Br J Haematol 2021; 196:724-734. [PMID: 34605011 DOI: 10.1111/bjh.17880] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/01/2021] [Accepted: 09/22/2021] [Indexed: 01/07/2023]
Abstract
Although telomere shortening is seen frequently in patients with aplastic anaemia (AA), there are no data on its association in matched sibling donor (MSD) transplants. We evaluated the effect of pre-transplant telomere length of patients and donors, measured by quantitative real-time polymerase chain reaction in 163 recipients undergoing MSD transplants. The median age of patients and donors was 24 and 26 years, respectively. Fludarabine and cyclophosphamide was the main conditioning regimen used and all received peripheral blood stem cell grafts. Engraftment occurred in 89% with graft failure (primary and secondary) in 6%. Acute and chronic graft-versus-host disease (GVHD) occurred in 28% and 24%, respectively. At a median follow-up of 37 months, 117 patients (72%) were alive. All patients and donors were divided into short and long telomere length based on their median and quartile values. Patient telomere length was not associated with severity of AA, neutrophil recovery, graft failure, acute GVHD or chronic GVHD. Longer donor telomere length was associated with better overall survival [hazard ratio (HR) = 0·2, P = 0·006] but did not influence neutrophil recovery, graft failure, acute or chronic GVHD. The five-year overall survival was significantly better (94·9 ± 3·5% vs 65·4 ± 4·3%, P = 0·002) for donors with long (highest quartile, DTL-HQ) versus short (lower three quartiles, DTL-LQ) telomeres, respectively. On multivariate analysis, longer donor telomere length, recipient age and acute GVHD continued to remain significant. This is the first study demonstrating an association of donor telomere length on overall survival following MSD transplant for AA but it needs to be confirmed in larger studies.
Collapse
Affiliation(s)
- Aruna Barade
- Department of Haematology, Christian Medical College Vellore, Vellore, India
| | - Fouzia Aboobacker
- Department of Haematology, Christian Medical College Vellore, Vellore, India
| | - Anu Korula
- Department of Haematology, Christian Medical College Vellore, Vellore, India
| | - Kavitha Lakshmi
- Department of Haematology, Christian Medical College Vellore, Vellore, India
| | - Anup Devasia
- Department of Haematology, Christian Medical College Vellore, Vellore, India
| | - Aby Abraham
- Department of Haematology, Christian Medical College Vellore, Vellore, India
| | - Vikram Mathews
- Department of Haematology, Christian Medical College Vellore, Vellore, India
| | - Eunice Edison
- Department of Haematology, Christian Medical College Vellore, Vellore, India
| | - Biju George
- Department of Haematology, Christian Medical College Vellore, Vellore, India
| |
Collapse
|
|
24
|
DNA-methylation-based telomere length estimator: comparisons with measurements from flow FISH and qPCR. Aging (Albany NY) 2021; 13:14675-14686. [PMID: 34083495 PMCID: PMC8221337 DOI: 10.18632/aging.203126] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 05/14/2021] [Indexed: 12/18/2022]
Abstract
Telomere length (TL) is a marker of biological aging associated with several health outcomes. High throughput reproducible TL measurements are needed for large epidemiological studies. We compared the novel DNA methylation-based estimator (DNAmTL) with the high-throughput quantitative PCR (qPCR) and the highly accurate flow cytometry with fluorescent in situ hybridization (flow FISH) methods using blood samples from healthy adults. We used Pearson’s correlation coefficient, Bland Altman plots and linear regression models for statistical analysis. Shorter DNAmTL was associated with older age, male sex, white race, and cytomegalovirus seropositivity (p<0.01 for all). DNAmTL was moderately correlated with qPCR TL (N=635, r=0.41, p < 0.0001) and flow FISH total lymphocyte TL (N=144, r=0.56, p < 0.0001). The agreements between flow FISH TL and DNAmTL or qPCR were acceptable but with wide limits of agreement. DNAmTL correctly classified >70% of TL categorized above or below the median, but the accuracy dropped with increasing TL categories. The ability of DNAmTL to detect associations with age and other TL-related factors in the absence of strong correlation with measured TL may indicate its capture of aspects of telomere maintenance mechanisms and not necessarily TL. The inaccuracy of DNAmTL prediction should be considered during data interpretation and across-study comparisons.
Collapse
|
|
25
|
Lin RJ, Elias HK, van den Brink MRM. Immune Reconstitution in the Aging Host: Opportunities for Mechanism-Based Therapy in Allogeneic Hematopoietic Cell Transplantation. Front Immunol 2021; 12:674093. [PMID: 33953731 PMCID: PMC8089387 DOI: 10.3389/fimmu.2021.674093] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 03/30/2021] [Indexed: 12/13/2022] Open
Abstract
Older patients with hematologic malignancies are increasingly considered for allogeneic hematopoietic cell transplantation with encouraging outcomes. While aging-related thymic dysfunction remains a major obstacle to optimal and timely immune reconstitution post- transplantation, recent accumulating evidence has suggested that various aging hallmarks such as cellular senescence, inflamm-aging, and hematopoietic stem cell exhaustion, could also impact immune reconstitution post-transplantation in both thymic-dependent and independent manner. Here we review molecular and cellular aspects of immune senescence and immune rejuvenation related to allogeneic hematopoietic cell transplantation among older patients and discuss potential strategies for mechanism-based therapeutic intervention.
Collapse
Affiliation(s)
- Richard J Lin
- Adult Bone Marrow Transplantation (BMT) Service, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, United States.,Department of Medicine, Weill Cornell Medical College, New York, NY, United States
| | - Harold K Elias
- Adult Bone Marrow Transplantation (BMT) Service, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, United States.,Department of Medicine, Weill Cornell Medical College, New York, NY, United States
| | - Marcel R M van den Brink
- Adult Bone Marrow Transplantation (BMT) Service, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, United States.,Department of Medicine, Weill Cornell Medical College, New York, NY, United States
| |
Collapse
|
|
26
|
Mackintosh JA, Yerkovich ST, Tan ME, Samson L, Hopkins PMA, Chambers DC. Airway Telomere Length in Lung Transplant Recipients. Front Immunol 2021; 12:658062. [PMID: 33936089 PMCID: PMC8085488 DOI: 10.3389/fimmu.2021.658062] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 03/30/2021] [Indexed: 11/13/2022] Open
Abstract
Introduction Chronic lung allograft dysfunction (CLAD) represents the major impediment to long term survival following lung transplantation. Donor and recipient telomere length have been shown to associate with lung transplant outcomes, including CLAD. In this study we aimed to measure the telomere lengths of bronchial and bronchiolar airway cells in lung allografts early after transplantation and to investigate associations with CLAD and all-cause mortality. Methods This prospective, longitudinal study was performed at The Prince Charles Hospital, Australia. Airway cells were collected via bronchial and bronchiolar airway brushings at post-transplant bronchoscopies. The relative telomere length in airway cells was determined by quantitative PCR based on the T/S ratio. All patients were censored for CLAD and all-cause mortality in August 2020. Results In total 231 bronchoscopies incorporating transbronchial brush and bronchial brush were performed in 120 patients. At the time of censoring, 43% and 35% of patients, respectively, had developed CLAD and had died. Airway bronchiolar and bronchial telomere lengths were strongly correlated (r=0.78, p<0.001), confirming conservation of telomere length with airway branch generation. Both the bronchiolar (r = -0.34, p<0.001) and bronchial (r = -0.31, p<0.001) telomere length decreased with age. Shorter airway telomere length was associated with older donor age and higher donor pack-year smoking history. Neither the bronchiolar nor the bronchial airway telomere length were associated with the development of CLAD (HR 0.39 (0.06-2.3), p=0.30; HR 0.66 (0.2-1.7), p=0.39, respectively) or all-cause mortality (HR 0.92 (0.2-4.5), p=0.92; HR 0.47 (0.1-1.9), p=0.28, respectively). Conclusions In this cohort, airway telomere length was associated with donor age and smoking history but was not associated with the future development of CLAD or all-cause mortality.
Collapse
Affiliation(s)
- John A. Mackintosh
- Queensland Lung Transplant Service, Department of Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD, Australia
| | - Stephanie T. Yerkovich
- Queensland Lung Transplant Service, Department of Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Maxine E. Tan
- Queensland Lung Transplant Service, Department of Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD, Australia
| | - Luke Samson
- Queensland Lung Transplant Service, Department of Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD, Australia
| | - Peter MA Hopkins
- Queensland Lung Transplant Service, Department of Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Daniel C. Chambers
- Queensland Lung Transplant Service, Department of Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| |
Collapse
|
|
27
|
Alsaggaf R, Katta S, Wang T, Hicks BD, Zhu B, Spellman SR, Lee SJ, Horvath S, Gadalla SM. Epigenetic Aging and Hematopoietic Cell Transplantation in Patients With Severe Aplastic Anemia. Transplant Cell Ther 2021; 27:313.e1-313.e8. [PMID: 33836872 PMCID: PMC8036238 DOI: 10.1016/j.jtct.2021.01.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 01/13/2021] [Indexed: 01/17/2023]
Abstract
Cellular aging in hematopoietic cell transplantation (HCT) is important in the context of immune reconstitution and age-related complications. Recently, several DNA-methylation (DNAm)-based biomarkers of aging known as "epigenetic clocks" have been introduced as novel tools to predict cellular age. Here, we used Cox proportional hazards models to assess the possible associations of donor pre-HCT DNAm age, and its post-HCT changes, using the recently published lifespan-associated epigenetic clock known as "DNAm-GrimAge," with outcomes among patients with severe aplastic anemia (SAA). The study included 732 SAA patients from the Transplant Outcomes in Aplastic Anemia project, who underwent unrelated donor HCT and for whom a donor pre-HCT blood DNA sample was available; 41 also had a post-HCT sample collected at day 100. In multivariable analyses, we found similar associations for donor chronological age and pre-HCT DNAm-GrimAge with post-HCT survival (hazard ratio [HR] per decade = 1.13; 95% confidence interval [CI], 0.99-1.28; P = .07 and HR = 1.14; 95% CI, 0.99-1.28; P = .06, respectively). In donors with 10+ years of GrimAge acceleration (ie, deviation from expected DNAm age for chronological age), elevated risks of chronic graft versus host disease (HR = 2.4; 95% CI, 1.21-4.65; P = .01) and possibly post-HCT mortality (HR = 1.79; 95% CI, 0.96-3.33; P = .07) were observed. In the subset with post-HCT samples, we observed a significant increase in DNAm-GrimAge in the first 100 days after HCT (median change 12.5 years, range 1.4 to 26.4). Higher DNAm-GrimAge after HCT was associated with inferior survival (HR per year = 1.11; 95% CI, 1.02-1.21; P = .01), predominantly within the first year after HCT. This study highlights the possible role cellular aging may play in HCT outcomes.
Collapse
Affiliation(s)
- Rotana Alsaggaf
- Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Shilpa Katta
- Cancer Genomics Research Laboratory, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Tao Wang
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Biostatistics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Belynda D Hicks
- Cancer Genomics Research Laboratory, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Bin Zhu
- Biostatistics Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Stephen R Spellman
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Stephanie J Lee
- Center for International Blood and Marrow Transplant Research, Minneapolis, Minnesota; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Steve Horvath
- David Geffen School of Medicine, University of California, Los Angeles, California
| | - Shahinaz M Gadalla
- Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
| |
Collapse
|
|
28
|
Hu D, Yuan S, Zhong J, Liu Z, Wang Y, Liu L, Li J, Wen F, Liu J, Zhang J. Cellular senescence and hematological malignancies: From pathogenesis to therapeutics. Pharmacol Ther 2021; 223:107817. [PMID: 33587950 DOI: 10.1016/j.pharmthera.2021.107817] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 02/07/2021] [Accepted: 02/09/2021] [Indexed: 12/24/2022]
Abstract
Cellular senescence constitutes a permanent state of cell cycle arrest in proliferative cells induced by different stresses. The exploration of tumor pathogenesis and therapies has been a research hotspot in recent years. Cellular senescence is a significant mechanism to prevent the proliferation of potential tumor cells, but it can also promote tumor growth. Increasing evidence suggests that cellular senescence is involved in the pathogenesis and development of hematological malignancies, including leukemia, myelodysplastic syndrome (MDS) and multiple myeloma (MM). Cellular senescence is associated with functional decline of hematopoietic stem cells (HSCs) and increased risk of hematological malignancies. Moreover, the bone marrow (BM) microenvironment has a crucial regulatory effect in the process of these diseases. The senescence-associated secretory phenotype (SASP) in the BM microenvironment establishes a protumor environment that supports the proliferation and survival of tumor cells. Therefore, a series of therapeutic strategies targeting cellular senescence have been gradually developed, including the induction of cellular senescence and elimination of senescent cells. This review systematically summarizes the emerging information describing the roles of cellular senescence in tumorigenesis and potential clinical applications, which may be beneficial for designing rational therapeutic strategies for various hematopoietic malignancies.
Collapse
Affiliation(s)
- Dingyu Hu
- Department of Clinical Laboratory, The First Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China
| | - Shunling Yuan
- Department of Clinical Laboratory, The First Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China
| | - Jing Zhong
- Institute of Clinical Medicine, First Affiliated Hospital of University of South China, Hengyang 421001, Hunan, China
| | - Zhaoping Liu
- Department of Clinical Laboratory, The First Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China
| | - Yanyan Wang
- Department of Clinical Laboratory, The First Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China
| | - Li Liu
- Department of Clinical Laboratory, The First Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China
| | - Junjun Li
- Department of Hematology, The First Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China
| | - Feng Wen
- Department of Hematology, The First Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China
| | - Jing Liu
- Hunan Province Key Laboratory of Basic and Applied Hematology, Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, Hunan, China.
| | - Ji Zhang
- Department of Clinical Laboratory, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong, China; Department of Clinical Laboratory, The First Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China.
| |
Collapse
|
|
29
|
Pan TD, Kanaan SB, Lee NR, Avila JL, Nelson JL, Eisenberg DTA. Predictors of maternal-origin microchimerism in young women in the Philippines. AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY 2021; 174:213-223. [PMID: 33300155 PMCID: PMC11753296 DOI: 10.1002/ajpa.24191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 09/17/2020] [Accepted: 11/09/2020] [Indexed: 11/07/2022]
Abstract
OBJECTIVES Microchimerism is the presence of a small quantity of cells or DNA from a genetically distinct individual. This phenomenon occurs with bidirectional maternal-fetal exchange during pregnancy. Microchimerism can persist for decades after delivery and have long-term health implications. However, little is known about why microchimerism is detectable at varying levels in different individuals. We examine the variability and the following potential determinants of maternal-origin microchimerism (MMc) in young women in the Philippines: gestational duration (in utero exposure to MMc), history of being breastfed (postpartum exposure to MMc), maternal telomere length (maternal cells' ability to replicate and persist), and participant's pregnancies in young adulthood (effect of adding fetal-origin microchimerism to preexisting MMc). MATERIALS AND METHODS Data are from the Cebu Longitudinal Health and Nutrition Survey, a population-based study of infant feeding practices and long-term health outcomes. We quantified MMc using quantitative PCR (qPCR) in 89 female participants, ages 20-22, and analyzed these data using negative binomial regression. RESULTS In a multivariate model including all predictors, being breastfed substantially predicted decreased MMc (detection rate ratio = 0.15, p = 0.007), and there was a trend of decreasing MMc in participants who had experienced more pregnancies (detection rate ratio = 0.55, p = 0.057). DISCUSSION These results might be explained by breastfeeding having lasting impact on immune regulatory networks, thus reducing MMc persistence. MMc may also decrease in response to the introduction of fetal-origin microchimerism with pregnancies experienced in adulthood.
Collapse
Affiliation(s)
- Tiffany D. Pan
- Department of Anthropology, University of Washington, Seattle, Washington
- Center for Studies in Demography and Ecology, University of Washington, Seattle, Washington
| | - Sami B. Kanaan
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Nanette R. Lee
- USC-Office of Population Studies Foundation, Inc., Cebu City, Philippines
- Department of Anthropology, Sociology & History, University of San Carlos, Cebu City, Philippines
| | - Josephine L. Avila
- USC-Office of Population Studies Foundation, Inc., Cebu City, Philippines
- Department of Architecture, School of Architecture, Fine Arts and Design, University of San Carlos, Cebu City, Philippines
| | - J. Lee Nelson
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Department of Medicine, University of Washington, Seattle, Washington
| | - Dan T. A. Eisenberg
- Department of Anthropology, University of Washington, Seattle, Washington
- Center for Studies in Demography and Ecology, University of Washington, Seattle, Washington
- Department of Biology, University of Washington, Seattle, Washington
| |
Collapse
|
|
30
|
Gadalla SM, Wang Y, Wang T, Onabajo OO, Banday AR, Obajemu A, Karaesman E, Sucheston-Campbell L, Hahn T, Sees JA, Spellman SR, Lee SJ, Katki HA, Prokunina-Olsson L. Association of donor IFNL4 genotype and non-relapse mortality after unrelated donor myeloablative haematopoietic stem-cell transplantation for acute leukaemia: a retrospective cohort study. LANCET HAEMATOLOGY 2020; 7:e715-e723. [PMID: 32976751 DOI: 10.1016/s2352-3026(20)30294-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 07/01/2020] [Accepted: 07/13/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND The interferon lambda 4 gene (IFNL4) regulates immune responses by controlling the production of IFNλ4, a type III interferon. We hypothesised that IFNλ4 could play a role in infection clearance or alloreactivity in patients with acute leukaemia who received a myeloablative 10/10 HLA-matched haematopoietic stem-cell transplantation (HSCT). Therefore, we aimed to assess the association between recipient and donor IFNL4 genotype with post-HSCT survival outcomes in patients with acute leukaemia. METHODS We did a two-stage retrospective cohort study using the Center for International Blood and Marrow Transplant Research (CIBMTR) repository and database, in which nearly all patients underwent the procedure in the USA. We included patients with acute myeloid leukaemia or acute lymphocytic leukaemia, who received a HSCT at any age from an unrelated 10/10 HLA-matched donor, with a myeloablative conditioning regimen, between Jan 1, 2000, and Dec 31, 2008, and had a pre-HSCT recipient or donor blood sample available. The discovery dataset included patients from an existing National Cancer Institute (NCI) cohort of the CIBMTR database, in which donor and recipient IFNL4 polymorphisms (rs368234815, rs12979860, and rs117648444) were genotyped with TaqMan assays. According to their genotype, donors and recipients were categorised into IFNL4-positive, if they had at least one copy of the allele that supports the production of IFNλ4, or IFNL4-null for the analyses. The findings were independently validated with patients from the DISCOVeRY-BMT cohort (validation dataset) with existing Illumina array genotype data. We also did a combined analysis using data from patients included in both the NCI and DISCOVeRY-BMT cohorts. FINDINGS We assessed 404 patients (who had a HSCT from Jan 9, 2004, to Dec 26, 2008) in the discovery dataset and 1245 patients in the validation dataset (HSCT Jan 7, 2000, to Dec 26, 2008). The combined analysis included 1593 overlapping participants in both cohorts. Donor, but not recipient IFNL4-positive genotype was associated with increased risk of non-relapse mortality (HR 1·60, 95% CI 1·23-2·10; p=0·0005 in the discovery dataset; 1·22, 1·05-1·40; p=0·0072 in the validation dataset; and 1·27, 1·12-1·45; p=0·0001 in the combined dataset). Associations with post-HSCT overall survival were as follows: HR 1·24, 95% CI 1·02-1·51; p=0·034 in the discovery dataset; 1·10, 0·98-1·20; p=0·10 in the validation dataset; and 1·11, 1·02-1·22; p=0·018 in the combined dataset. INTERPRETATION Prioritising HSCT donors with the IFNL4-null genotype might decrease non-relapse mortality and improve overall survival without substantially limiting the donor pool. If these findings are validated, IFNL4 genotype could be added to the donor selection algorithm. FUNDING The National Cancer Institute Intramural Research Program. For full funding list see Acknowledgments.
Collapse
Affiliation(s)
- Shahinaz M Gadalla
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.
| | - Youjin Wang
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Tao Wang
- Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, USA; Center for International Blood and Marrow Transplant Research Milwaukee, WI, USA
| | - Olusegun O Onabajo
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA
| | - A Rouf Banday
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Adeola Obajemu
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Ezgi Karaesman
- College of Pharmacy, Ohio State University Columbus, OH, USA
| | | | - Theresa Hahn
- Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Jennifer A Sees
- Center for International Blood and Marrow Transplant Research, Minneapolis, MN, USA
| | - Stephen R Spellman
- Center for International Blood and Marrow Transplant Research, Minneapolis, MN, USA
| | - Stephanie J Lee
- Center for International Blood and Marrow Transplant Research Milwaukee, WI, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Hormuzd A Katki
- Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA
| | - Ludmila Prokunina-Olsson
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA
| |
Collapse
|
|
31
|
Courtwright AM, Lamattina AM, Takahashi M, Trindade AJ, Hunninghake GM, Rosas IO, Agarwal S, Raby BA, Goldberg HJ, El-Chemaly S. Shorter telomere length following lung transplantation is associated with clinically significant leukopenia and decreased chronic lung allograft dysfunction-free survival. ERJ Open Res 2020; 6:00003-2020. [PMID: 32577419 PMCID: PMC7293991 DOI: 10.1183/23120541.00003-2020] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Accepted: 03/26/2020] [Indexed: 01/11/2023] Open
Abstract
Patients with short telomeres and interstitial lung disease may have decreased chronic lung allograft dysfunction (CLAD)-free survival following lung transplantation. The relationship between post-transplant telomere length and outcomes following lung transplantation has not been characterised among all recipients, regardless of native lung disease. This was a single-centre prospective cohort study. Consenting transplant recipients had their telomere length measured using quantitative real-time PCR assays on peripheral blood collected at the time of surveillance bronchoscopy. We assessed the association between early post-transplant telomere length (as measured in the first 100 days) and CLAD-free survival, time to clinically significant leukopenia, cytomegalovirus (CMV) viraemia, chronic kidney disease, and acute cellular rejection. We also assessed the association between rate of telomere shortening and CLAD-free survival. Telomere lengths were available for 98 out of 215 (45.6%) recipients who underwent lung transplant during the study period (median measurement per patient=2 (interquartile range, 1–3)). Shorter telomere length was associated with decreased CLAD-free survival (hazard ratio (HR)=1.24; 95% CI=1.03–1.48; p=0.02), leukopenia requiring granulocyte colony-stimulating factor (HR=1.17, 95% CI=1.01–1.35, p=0.03), and CMV viraemia among CMV-mismatch recipients (HR=4.04, 95% CI=1.05–15.5, p=0.04). Telomere length was not associated with acute cellular rejection or chronic kidney disease. Recipients with more rapid loss in telomere length (defined as the highest tertile of telomere shortening) did not have worse subsequent CLAD-free survival than those without rapid loss (HR=1.38, 95% CI=0.27–7.01, p=0.70). Shorter early post-transplant telomere length is associated with decreased CLAD-free survival and clinically significant leukopenia in lung transplant recipients, regardless of native lung disease. Shorter recipient telomere length following lung transplantation is associated with clinically significant leukopenia and decreased chronic lung allograft dysfunction-free survivalhttps://bit.ly/2ytymXc
Collapse
Affiliation(s)
- Andrew M Courtwright
- Dept of Pulmonary and Critical Care Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Anthony M Lamattina
- Division of Pulmonary and Critical Care, Brigham and Women's Hospital, Boston, MA, USA
| | - Mai Takahashi
- Harvard T.H. Chen School of Public Health, Boston, MA, USA
| | - Anil J Trindade
- Division of Pulmonary and Critical Care, Brigham and Women's Hospital, Boston, MA, USA
| | - Gary M Hunninghake
- Division of Pulmonary and Critical Care, Brigham and Women's Hospital, Boston, MA, USA
| | - Ivan O Rosas
- Division of Pulmonary and Critical Care, Brigham and Women's Hospital, Boston, MA, USA
| | - Suneet Agarwal
- Division of Hematology/Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston Children's Hospital, Boston, MA, USA
| | - Benjamin A Raby
- Division of Pulmonary and Critical Care, Brigham and Women's Hospital, Boston, MA, USA.,Division of Pulmonary Medicine, Boston Children's Hospital, Boston, MA, USA.,Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Hilary J Goldberg
- Division of Pulmonary and Critical Care, Brigham and Women's Hospital, Boston, MA, USA
| | - Souheil El-Chemaly
- Division of Pulmonary and Critical Care, Brigham and Women's Hospital, Boston, MA, USA
| |
Collapse
|
|
32
|
Zia MA. Streptokinase: An Efficient Enzyme in Cardiac Medicine. Protein Pept Lett 2020; 27:111-119. [PMID: 31612811 DOI: 10.2174/0929866526666191014150408] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 04/22/2019] [Accepted: 08/06/2019] [Indexed: 01/27/2023]
Abstract
An imbalance in oxygen supply to cardiac tissues or formation of thrombus leads to deleterious results like pulmonary embolism, coronary heart disease and acute cardiac failure. The formation of thrombus requires clinical encounter with fibrinolytic agents including streptokinase, urokinase or tissue plasminogen activator. Irrespective to urokinase and tissue plasminogen activator, streptokinase is still a significant agent in treatment of cardiovascular diseases. Streptokinase, being so economical, has an important value in treating cardiac diseases in developing countries. This review paper will provide the maximum information to enlighten all the pros and cons of streptokinase up till now. It has been concluded that recent advances in structural/synthetic biology improved SK with enhanced half-life and least antigenicity. Such enzyme preparations would be the best thrombolytic agents.
Collapse
Affiliation(s)
- Muhammad A Zia
- Enzyme Biotechnology Laboratory, Department of Biochemistry, University of Agriculture, Faisalabad-38040,Pakistan
| |
Collapse
|
|
33
|
Brzeźniakiewicz-Janus K, Rupa-Matysek J, Gil L. Acquired Aplastic Anemia as a Clonal Disorder of Hematopoietic Stem Cells. Stem Cell Rev Rep 2020; 16:472-481. [PMID: 32270433 PMCID: PMC7253510 DOI: 10.1007/s12015-020-09971-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Aplastic anemia is rare disorder presenting with bone marrow failure syndrome due to autoimmune destruction of early hematopoietic stem cells (HSCs) and stem cell progenitors. Recent advances in newer genomic sequencing and other molecular techniques have contributed to a better understanding of the pathogenesis of aplastic anemia with respect to the inflammaging, somatic mutations, cytogenetic abnormalities and defective telomerase functions of HSCs. These have been summarized in this review and may be helpful in differentiating aplastic anemia from hypocellular myelodysplastic syndrome. Furthermore, responses to immunosuppressive therapy and outcomes may be determined by molecular pathogenesis of HSCs autoimmune destruction, as well as treatment personalization in the future.
Collapse
Affiliation(s)
- Katarzyna Brzeźniakiewicz-Janus
- Department of Hematology, Multi-Specialist Hospital Gorzów Wielkopolski, Faculty of Medicine and Health Science, University of Zielona Góra, Gorzów Wielkopolski, Poland.
| | - Joanna Rupa-Matysek
- Department of Hematology and Bone Marrow Transplantation, Poznań University of Medical Sciences, Poznań, Poland
| | - Lidia Gil
- Department of Hematology and Bone Marrow Transplantation, Poznań University of Medical Sciences, Poznań, Poland
| |
Collapse
|
|
34
|
McReynolds LJ, Wang Y, Thompson AS, Ballew BJ, Kim J, Alter BP, Hicks B, Zhu B, Jones K, Spellman SR, Wang T, Lee SJ, Savage SA, Gadalla SM. Population Frequency of Fanconi Pathway Gene Variants and Their Association with Survival After Hematopoietic Cell Transplantation for Severe Aplastic Anemia. Biol Blood Marrow Transplant 2020; 26:817-822. [PMID: 31982544 PMCID: PMC7243455 DOI: 10.1016/j.bbmt.2020.01.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 01/09/2020] [Accepted: 01/15/2020] [Indexed: 11/17/2022]
Abstract
Severe aplastic anemia (SAA) is most frequently immune-mediated; however, rare inherited bone marrow failure syndromes, such as Fanconi anemia (FA), may be causal and can present as aplastic anemia (AA). FA is primarily an autosomal recessive disorder caused by the presence of 2 pathogenic variants in a single FA/BRCA DNA repair pathway gene. Patients with SAA often undergo genetic testing during clinical evaluation that may identify single deleterious alleles in FA pathway genes. We quantified the rate of germline single deleterious alleles in 22 FA genes using both a general population database (3234 variants, 125,748 exomes) and in a cohort of patients with SAA undergoing hematopoietic cell transplantation (HCT) (21 variants in 730 patients). The variants were classified as deleterious using in silico tools (REVEL, MetaSVM, VEP) and database resources (ClinVar, LOVD-FA). We found similar rates of single deleterious alleles in FA genes in both groups (2.6% and 2.9%). The presence of a single deleterious variant in a gene for FA in SAA HCT recipients did not affect the overall survival after HCT (hazard ratio, 0.85; 95% CI, 0.37 to 1.95; P = 0.71), or post-HCT cancer risk (P = 0.52). Our results demonstrate that the identification of a germline monoallelic deleterious variant in an FA gene in patients with idiopathic SAA does not influence the outcome of HCT. Our findings suggest that there is no need for special treatment considerations for patients with SAA and a single deleterious FA allele identified on genetic testing.
Collapse
Affiliation(s)
- Lisa J McReynolds
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
| | - Youjin Wang
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Ashley S Thompson
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Bari J Ballew
- Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland; Leidos Biomedical Research, Inc. Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Jung Kim
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Blanche P Alter
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Belynda Hicks
- Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland; Leidos Biomedical Research, Inc. Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Bin Zhu
- Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland; Leidos Biomedical Research, Inc. Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Kristine Jones
- Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland; Leidos Biomedical Research, Inc. Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Stephen R Spellman
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Biostatistics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Tao Wang
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Biostatistics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Stephanie J Lee
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Sharon A Savage
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Shahinaz M Gadalla
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| |
Collapse
|
|
35
|
Lee GH, Hong KT, Choi JY, Shin HY, Lee WW, Kang HJ. Immunosenescent characteristics of T cells in young patients following haploidentical haematopoietic stem cell transplantation from parental donors. Clin Transl Immunology 2020; 9:e1124. [PMID: 32280463 PMCID: PMC7142179 DOI: 10.1002/cti2.1124] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 03/03/2020] [Accepted: 03/06/2020] [Indexed: 12/17/2022] Open
Abstract
Objectives Paediatric and adolescent patients in need of allogeneic haematopoietic stem cell transplantation (HSCT) generally receive stem cells from older, unrelated or parental donors when a sibling donor is not available. Despite encouraging clinical outcomes, it has been suggested that immune reconstitution accompanied by increased replicative stress and a large difference between donor and recipient age may worsen immunosenescence in paediatric recipients. Methods In this study, paired samples were collected at the same time from donors and recipients of haploidentical haematopoietic stem cell transplantation (HaploSCT). We then conducted flow cytometry‐based phenotypic and functional analyses and telomere length (TL) measurements of 21 paired T‐cell sets from parental donors and children who received T‐cell‐replete HaploSCT with post‐transplant cyclophosphamide (PTCy). Results Senescent T cells, CD28− or CD57+ cells, were significantly expanded in patients. Further, not only CD4+CD28− T cells, but also CD4+CD28+ T cells showed reduced cytokine production capacity and impaired polyfunctionality compared with parental donors, whereas their TCR‐mediated proliferation capacity was comparable. Of note, the TL in patient T cells was preserved, or even slightly longer, in senescent T cells compared with donor cells. Regression analysis showed that senescent features of CD4+ and CD8+ T cells in patients were influenced by donor age and the frequency of CD28− cells, respectively. Conclusion Our data suggest that in paediatric HaploSCT, premature immunosenescent changes occur in T cells from parental donors, and therefore, long‐term immune monitoring should be conducted.
Collapse
Affiliation(s)
- Ga Hye Lee
- Department of Biomedical Sciences Seoul National University College of Medicine Seoul South Korea.,BK21Plus Biomedical Science Project Seoul National University College of Medicine Seoul South Korea
| | - Kyung Taek Hong
- Department of Pediatrics Seoul National University College of Medicine Seoul South Korea.,Seoul National University Cancer Research Institute Seoul South Korea
| | - Jung Yoon Choi
- Department of Pediatrics Seoul National University College of Medicine Seoul South Korea.,Seoul National University Cancer Research Institute Seoul South Korea
| | - Hee Young Shin
- Department of Pediatrics Seoul National University College of Medicine Seoul South Korea.,Seoul National University Cancer Research Institute Seoul South Korea
| | - Won-Woo Lee
- Department of Biomedical Sciences Seoul National University College of Medicine Seoul South Korea.,BK21Plus Biomedical Science Project Seoul National University College of Medicine Seoul South Korea.,Seoul National University Cancer Research Institute Seoul South Korea.,Department of Microbiology and Immunology Seoul National University College of Medicine Seoul South Korea.,Ischemic/Hypoxic Disease Institute Seoul National University College of Medicine Seoul South Korea.,Institute of Infectious Diseases Seoul National University College of Medicine Seoul South Korea.,Seoul National University Hospital Biomedical Research Institute Seoul South Korea
| | - Hyoung Jin Kang
- Department of Pediatrics Seoul National University College of Medicine Seoul South Korea.,Seoul National University Cancer Research Institute Seoul South Korea
| |
Collapse
|
|
36
|
Schratz KE, DeZern AE. Genetic Predisposition to Myelodysplastic Syndrome in Clinical Practice. Hematol Oncol Clin North Am 2020; 34:333-356. [PMID: 32089214 PMCID: PMC7875473 DOI: 10.1016/j.hoc.2019.10.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Myelodysplastic syndromes (MDSs) are a heterogeneous group of marrow failure disorders that primarily affect older persons but also occur at a lower frequency in children and young adults. There is increasing recognition of an inherited predisposition to MDS as well as other myeloid malignancies for patients of all ages. Germline predisposition to MDS can occur as part of a syndrome or sporadic disease. The timely diagnosis of an underlying genetic predisposition in the setting of MDS is important. This article delineates germline genetic causes of MDS and provides a scaffold for the diagnosis and management of patients in this context.
Collapse
Affiliation(s)
- Kristen E Schratz
- Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Bloomberg 11379, 1800 Orleans Street, Baltimore, MD 21287, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21287, USA
| | - Amy E DeZern
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21287, USA; Division of Hematologic Malignancies, Johns Hopkins University School of Medicine, CRBI Room 3M87, 1650 Orleans Street, Baltimore, MD 21287-0013, USA.
| |
Collapse
|
|
37
|
Fei Y, Hu XX, Chen Q, Huang AJ, Cheng H, Ni X, Chen L, Gao L, Tang GS, Chen J, Zhang WP, Yang JM, Wang JM. [Risk-factors analysis of graft failure after allogeneic hematopoietic stem cell transplantation]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2020; 41:64-68. [PMID: 32023757 PMCID: PMC7357917 DOI: 10.3760/cma.j.issn.0253-2727.2020.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Indexed: 11/05/2022]
Affiliation(s)
- Y Fei
- Department of Hematology, Institute of Hematology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - X X Hu
- Department of Hematology, Institute of Hematology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Q Chen
- Department of Health Statistics, Second Military Medical University, Shanghai 200433, China
| | - A J Huang
- Department of Hematology, Institute of Hematology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - H Cheng
- Department of Hematology, Institute of Hematology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - X Ni
- Department of Hematology, Institute of Hematology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - L Chen
- Department of Hematology, Institute of Hematology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - L Gao
- Department of Hematology, Institute of Hematology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - G S Tang
- Department of Hematology, Institute of Hematology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - J Chen
- Department of Hematology, Institute of Hematology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - W P Zhang
- Department of Hematology, Institute of Hematology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - J M Yang
- Department of Hematology, Institute of Hematology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - J M Wang
- Department of Hematology, Institute of Hematology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| |
Collapse
|
|
38
|
Wang T, Fu R. [Interactions between clonality and aplastic anemia]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2019; 40:965-968. [PMID: 31856451 PMCID: PMC7342366 DOI: 10.3760/cma.j.issn.0253-2727.2019.11.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Indexed: 12/01/2022]
Affiliation(s)
- T Wang
- Department of Hematology, General Hospital, Tianjin Medical University, Tianjin 300052, China
| | | |
Collapse
|
|
39
|
Swaminathan AC, Neely ML, Frankel CW, Kelly FL, Petrovski S, Durheim MT, Bush E, Snyder L, Goldstein DB, Todd JL, Palmer SM. Lung Transplant Outcomes in Patients With Pulmonary Fibrosis With Telomere-Related Gene Variants. Chest 2019; 156:477-485. [DOI: 10.1016/j.chest.2019.03.030] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 01/10/2019] [Accepted: 03/01/2019] [Indexed: 01/21/2023] Open
|
|
40
|
Wang Y, McReynolds LJ, Dagnall C, Katki HA, Spellman SR, Wang T, Hicks B, Freedman ND, Jones K, Lee SJ, Savage SA, Gadalla SM. Pre-transplant short telomeres are associated with high mortality risk after unrelated donor haematopoietic cell transplant for severe aplastic anaemia. Br J Haematol 2019; 188:309-316. [PMID: 31426123 DOI: 10.1111/bjh.16153] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 06/20/2019] [Indexed: 11/28/2022]
Abstract
Telomeres are essential for chromosomal stability and markers of biological age. We evaluated the effect of pre-transplant short (<10th percentile-for-age) or very short (<5th or <1st percentile-for-age) leucocyte telomere length on survival after unrelated donor haematopoietic cell transplantation (HCT) for acquired severe aplastic anaemia (SAA). Patient pre-transplant blood samples and clinical data were available at the Center for International Blood and Marrow Transplant Research. We used quantitative real time polymerase chain reaction to measure relative telomere length (RTL) in 490 SAA patients who received HCT between 1990 and 2013 (median age = 20 years). One hundred and twelve patients (22·86%) had pre-HCT RTL <10th percentile-for-age, with the majority below the 5th percentile (N = 80, 71·43%). RTL <10th percentile-for-age was associated with a higher risk of post-HCT mortality (hazard ratio [HR] = 1·78, 95% confidence interval [CI]=1·18-2·69, P = 0·006) compared with RTL ≥50th percentile; no survival differences were noted in longer RTL categories (P > 0·10). Time-dependent effects for post-HCT mortality were only observed in relation to very short RTL; HR comparing RTL <5th versus ≥5th percentile = 1·38, P = 0·15 for the first 12 months after HCT, and HR = 3·91, P < 0·0001, thereafter, P-heterogeneity = 0·008; the corresponding HRs for RTL <1st versus ≥1st percentile = 1·29, P = 0·41, and HR = 5·18, P < 0·0001, P-heterogeneity = 0·005. The study suggests a potential role for telomere length in risk stratification of SAA patients in regard to their HCT survival.
Collapse
Affiliation(s)
- Youjin Wang
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Lisa J McReynolds
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Casey Dagnall
- Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.,Leidos Biomedical Research, Inc. Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Hormuzd A Katki
- Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Stephen R Spellman
- Center for International Blood and Marrow Transplant Research, Minneapolis, MN, USA
| | - Tao Wang
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA.,Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Belynda Hicks
- Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.,Leidos Biomedical Research, Inc. Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Neal D Freedman
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Kristine Jones
- Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.,Leidos Biomedical Research, Inc. Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Stephanie J Lee
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA.,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Sharon A Savage
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Shahinaz M Gadalla
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| |
Collapse
|
|
41
|
Derenzini E, Risso A, Ruella M, Spatola T, Milone G, Pioltelli P, Iori AP, Santarone S, Bosi A, Rambaldi A, Bacigalupo AP, Arcese W, Tarella C. Influence of Donor and Recipient Gender on Telomere Maintenance after Umbilical Cord Blood Cell Transplantation: A Study by the Gruppo Italiano Trapianto Di Midollo Osseo. Biol Blood Marrow Transplant 2019; 25:1387-1394. [PMID: 30935966 DOI: 10.1016/j.bbmt.2019.03.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Accepted: 03/24/2019] [Indexed: 12/13/2022]
Abstract
Physiologic loss of telomerase activity in adult life determines progressive telomere length (TL) shortening. Inflammation and oxidative damage are established causes of TL loss; moreover, males have shorter telomeres compared with females. Despite these notions, mechanisms regulating TL maintenance are poorly defined. Because umbilical cord blood (UCB) cells harbor very long telomeres, not yet exposed to environmental damages, UCB transplantation (UCBT) provides a unique experimental setting to study determinants of TL in humans. TL dynamics were analyzed on peripheral blood mononuclear cells (MNCs) from 36 patients (median age, 42 years) undergoing UCBT. TL was studied at a median of 20 months after UCBT. A significantly longer TL (mean, 8698 bp; range, 6521 to 11,960) was documented in UCBT recipients compared with age-matched healthy control subjects (mean, 7396 bp; range, 4375 to 11,108; P < .01). Among variables potentially influencing TL maintenance, including recipient features, graft type, transplant procedure, and engraftment kinetics, only donor-recipient gender combination was associated with TL, with the longest TL in women receiving male UCB (mean, 10,063 bp; range, 8381 to 11,960). To further investigate this trend, telomerase activation was assessed in vitro. Experiments showed that telomerase subunits were preferentially upregulated in male-derived bone marrow MNCs exposed ex vivo to estradiol as compared with female MNCs. This implies an increased sensitivity of male-derived MNCs to telomerase activation induced by estradiol. The results suggest that extrinsic and modifiable factors such as hormonal status and female milieu could be major determinants of TL in humans, providing the rationale for investigating hormonal-based approaches to counteract telomere erosion and aging-related diseases.
Collapse
Affiliation(s)
- Enrico Derenzini
- Oncohematology Division, IEO European Institute of Oncology, IRCCS, Milan, Italy
| | - Alessandra Risso
- Molecular Biotechnology Center Hematology & Cell Therapy Unit at Mauriziano H., Torino, Italy
| | - Marco Ruella
- Center for Cellular Immunotherapies & Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Tiziana Spatola
- Molecular Biotechnology Center Hematology & Cell Therapy Unit at Mauriziano H., Torino, Italy
| | - Giuseppe Milone
- Hematology and BMT Unit, Ospedale Ferrarotto, Catania, Italy
| | | | - Anna Paola Iori
- Division of Hematology, Department of Cellular Biotech & Hematol, 'Sapienza' University, Rome, Italy
| | - Stella Santarone
- Bone Marrow Transplant Center, Spirito Santo Hospital, Pescara, Italy
| | - Alberto Bosi
- Hematology Department, University of Florence and AOU Careggi, Florence, Italy
| | - Alessandro Rambaldi
- Department of Oncology and Hematology, ASST Papa Giovanni XXIII, Bergamo, Italy; University of Milan, Milan, Italy
| | | | - William Arcese
- Hematology Division-Stem Cell Transplant Unit, University of Rome Tor Vergata, Rome, Italy
| | - Corrado Tarella
- Oncohematology Division, IEO European Institute of Oncology, IRCCS, Milan, Italy; University of Milan, Milan, Italy.
| |
Collapse
|
|
42
|
Liu B, Anno K, Kobayashi T, Piao J, Tahara H, Ohdan H. Influence of donor liver telomere and G-tail on clinical outcome after living donor liver transplantation. PLoS One 2019; 14:e0213462. [PMID: 30845248 PMCID: PMC6405121 DOI: 10.1371/journal.pone.0213462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 02/19/2019] [Indexed: 11/26/2022] Open
Abstract
It has been reported that donor age affects patient outcomes after liver transplantation, and that telomere length is associated with age. However, to our knowledge, the impact of donor age and donor liver telomere length in liver transplantation has not been well investigated. This study aimed to clarify the influence of the length of telomere and G-tail from donor livers on the outcomes of living donors and recipients after living donor liver transplantation. The length of telomere and G-tail derived from blood samples and liver tissues of 55 living donors, measured using the hybridization protection assay. The length of telomeres from blood samples was inversely correlated with ages, whereas G-tail length from blood samples and telomere and G-tail lengths from liver tissues were not correlated with ages. Age, telomere, and G-tail length from blood did not affect postoperative liver failure and early liver regeneration of donors. On the other hand, the longer the liver telomere, the poorer the liver regeneration tended to be, especially with significant difference in donor who underwent right hemihepatectomy. We found that the survival rate of recipients who received liver graft with longer telomeres was inferior to that of those who received liver graft with shorter ones. An elderly donor, longer liver telomere, and higher Model for End-Stage Liver Disease score were identified as independent risk factors for recipient survival after transplantation. In conclusion, telomere shortening in healthy liver does not correlate with age, whereas longer liver telomeres negatively influence donor liver regeneration and recipient survival after living donor liver transplantation. These results can direct future studies and investigations on telomere shortening in the clinical and experimental transplant setting.
Collapse
Affiliation(s)
- Biou Liu
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kumiko Anno
- Department of Cellular and Molecular Biology, Graduate School of Pharmaceutical Sciences, Hiroshima University, Hiroshima, Japan
| | - Tsuyoshi Kobayashi
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- * E-mail:
| | - Jinlian Piao
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hidetoshi Tahara
- Department of Cellular and Molecular Biology, Graduate School of Pharmaceutical Sciences, Hiroshima University, Hiroshima, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| |
Collapse
|
|
43
|
Kennedy VE, Muffly LS. Assessment of older adult candidates for allogeneic hematopoietic cell transplantation: updates and remaining questions. Expert Rev Hematol 2019; 12:99-106. [DOI: 10.1080/17474086.2019.1568236] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Vanessa E. Kennedy
- Department of Internal Medicine, Division of Hospital Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Lori S. Muffly
- Department of Internal Medicine, Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA, USA
| |
Collapse
|
|
44
|
Zhang MW, Zhao P, Yung WH, Sheng Y, Ke Y, Qian ZM. Tissue iron is negatively correlated with TERC or TERT mRNA expression: A heterochronic parabiosis study in mice. Aging (Albany NY) 2018; 10:3834-3850. [PMID: 30555055 PMCID: PMC6326661 DOI: 10.18632/aging.101676] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 11/18/2018] [Indexed: 12/21/2022]
Abstract
To test the hypothesis that iron accumulation in tissues with age is a key harmful factor for the development of aging, we established heterochronic parabiosis-pairings and investigated changes in serum iron, the expression of major iron transport proteins and iron contents, as well as telomerase reverse transcriptase (TERT), telomerase RNA component (TERC), and telomere length in the liver, kidney and heart of Y-O(O) (old pairing with young), Y-O(Y) (young pairing with old), O-O (pairings between two old) and Y-Y (pairings between two young) mice. We demonstrated that the reduced serum iron, increased iron and reduced expression of TERT and TERC in the tissues of aged mice are reversible by exposure to a younger mouse’s circulation. All of these measurements in young mice are reversible by exposure to an older mouse’s circulation. Correlation analysis showed that tissue iron is negatively correlated with TERT and TERC expression in the liver, kidney and heart of parabiotic mice. These findings provide new evidence for the key role of iron in aging and also imply the existence of rejuvenating factors in young serum with an anti-ageing role that act by reversing the impaired activity of iron metabolism in old mice.
Collapse
Affiliation(s)
- Meng-Wan Zhang
- National Clinical Research Center for Aging and Medicine, Huashan Hostital, Laboratory of Neuropharmacology, School of Pharmacy, Fudan University, Shanghai 201203, PRC
| | - Peng Zhao
- National Clinical Research Center for Aging and Medicine, Huashan Hostital, Laboratory of Neuropharmacology, School of Pharmacy, Fudan University, Shanghai 201203, PRC
| | - Wing-Ho Yung
- School of Biomedical Sciences and Gerald Choa Neuroscience Centre, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong
| | - Yuan Sheng
- National Clinical Research Center for Aging and Medicine, Huashan Hostital, Laboratory of Neuropharmacology, School of Pharmacy, Fudan University, Shanghai 201203, PRC
| | - Ya Ke
- School of Biomedical Sciences and Gerald Choa Neuroscience Centre, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong
| | - Zhong-Ming Qian
- National Clinical Research Center for Aging and Medicine, Huashan Hostital, Laboratory of Neuropharmacology, School of Pharmacy, Fudan University, Shanghai 201203, PRC.,Laboratory of Neuropharmacology, Institute of Translational & Precision Medicine, Nantong University, Nantong 226019, PRC
| |
Collapse
|
|
45
|
Telomere Length Calibration from qPCR Measurement: Limitations of Current Method. Cells 2018; 7:cells7110183. [PMID: 30352968 PMCID: PMC6262465 DOI: 10.3390/cells7110183] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 10/19/2018] [Accepted: 10/21/2018] [Indexed: 12/21/2022] Open
Abstract
Telomere length (TL) comparisons from different methods are challenging due to differences in laboratory techniques and data configuration. This study aimed to assess the validity of converting the quantitative polymerase chain reaction (qPCR) telomere/single copy gene (T/S) ratio to TL in kilobases (kb). We developed a linear regression equation to predict TL from qPCR T/S using flow cytometry with fluorescence in situ hybridization (flow FISH) TL data from 181 healthy donors (age range = 19⁻53) from the National Marrow Donor Program (NMDP) biorepository. TL measurements by qPCR and flow FISH were modestly correlated (R² = 0.56, p < 0.0001). In Bland-Altman analyses, individuals with the shortest (≤10th percentile) or longest (≥90th) flow FISH TL had an over- or under-estimated qPCR TL (bias = 0.89 and -0.77 kb, respectively). Comparisons of calculated TL from the NMDP samples and 1810 age- and sex-matched individuals from the National Health and Nutrition Examination Survey showed significant differences (median = 7.1 versus 5.8 kb, respectively, p < 0.0001). Differences in annual TL attrition were also noted (31 versus 13 bp/year, respectively, p = 0.02). Our results demonstrate that TL calculated in kb from qPCR T/S may yield biased estimates for individuals with the shortest or longest TL, those often of high clinical interest. We also showed that calculated TL in kb from qPCR data are not comparable across populations and therefore are not necessarily useful.
Collapse
|
|
46
|
Abstract
Telomere length measurement is increasingly recognized as a clinical gauge for age-related disease risk. There are several methods for studying blood telomere length (BTL) as a clinical biomarker. The first is an observational study approach, which directly measures telomere lengths using either cross-sectional or longitudinal patient cohorts and compares them to a population of age- and sex-matched individuals. These direct traceable measurements can be considered reflective of an individual's current health or disease state. Escalating interest in personalized medicine, access to high-throughput genotyping and resulting acquisition of large volumes of genetic data corroborates the second method, Mendelian randomization (MR). MR employs telomere length-associated genetic variants to indicate predisposition to disease risk based on the genomic composition of the individual. When assessed from cells in the bloodstream, telomeres can show variation from their genetically predisposed lengths due to environmental-induced changes. These alterations in telomere length act as an indicator of cellular health, which, in turn, can provide disease risk status. Overall, BTL measurement is a dynamic marker of biological health and well-being that together with genetically defined telomere lengths can provide insights into improved healthcare for the individual.
Collapse
|
|
47
|
Helby J, Petersen SL, Kornblit B, Nordestgaard BG, Mortensen BK, Bojesen SE, Sengeløv H. Mononuclear Cell Telomere Attrition Is Associated with Overall Survival after Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies. Biol Blood Marrow Transplant 2018; 25:496-504. [PMID: 30266676 DOI: 10.1016/j.bbmt.2018.09.025] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 09/20/2018] [Indexed: 11/25/2022]
Abstract
After allogeneic hematopoietic cell transplantation (allo-HCT), transplanted cells rapidly undergo multiple rounds of division. This may cause extensive telomere attrition, which could potentially prohibit further cell division and lead to increased mortality. We therefore characterized the development in telomere length after nonmyeloablative allo-HCT in 240 consecutive patients transplanted because of hematologic malignancies and tested the hypothesis that extensive telomere attrition post-transplant is associated with low overall survival. Telomere length was measured using quantitative PCR in mononuclear cells obtained from donors and recipients pretransplant and in follow-up samples from recipients post-transplant. Telomere attrition at 9 to 15 months post-transplant was calculated as the difference between recipient telomere length at 9 to 15 months post-transplant and donor pretransplant telomere length, divided by donor pretransplant telomere length. Although allo-HCT led to shorter mean telomere length in recipients when compared with donors, recipients had longer mean telomere length 9 to 15 months post-transplant than they had pretransplant. When compared with donor telomeres, recipients with extensive telomere attrition at 9 to 15 months post-transplant had low overall survival (10-year survival from 9 to 15 months post-transplant and onward: 68% in the tertile with least telomere attrition, 57% in the middle tertile, and 39% in the tertile with most attrition; log-rank P = .01). Similarly, after adjusting for potential confounders, recipients with extensive telomere attrition had high all-cause mortality (multivariable adjusted hazard ratio, 1.84 per standard deviation of telomere attrition at 9 to 15 months post-transplant; 95% confidence interval, 1.25 to 2.72; P = .002) and high relapse-related mortality (subhazard ratio, 2.07; 95% confidence interval, 1.14 to 3.76; P = .02). Taken together, telomere attrition may be a clinically relevant marker for identifying patients at high risk of mortality.
Collapse
Affiliation(s)
- Jens Helby
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
| | - Søren Lykke Petersen
- Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Brian Kornblit
- Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Børge G Nordestgaard
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bo Kok Mortensen
- Department of Hematology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
| | - Stig E Bojesen
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Henrik Sengeløv
- Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
48
|
Rachakonda S, Srinivas N, Mahmoudpour SH, Garcia-Casado Z, Requena C, Traves V, Soriano V, Cardelli M, Pjanova D, Molven A, Gruis N, Nagore E, Kumar R. Telomere length and survival in primary cutaneous melanoma patients. Sci Rep 2018; 8:10947. [PMID: 30026606 PMCID: PMC6053393 DOI: 10.1038/s41598-018-29322-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 07/10/2018] [Indexed: 01/16/2023] Open
Abstract
Telomere repeats at chromosomal ends, critical to genomic integrity, undergo age-dependent attrition. Telomere length, a polygenic trait, has been associated with risk of several disorders including cancers. In contrast to association of long telomeres with increased risk of several cancers, including melanoma, emerging reports suggest that short telomeres predict poor survival in patients with different cancers. In this study based on 1019 stage I and II cutaneous melanoma patients, we show an association between the patients with short telomeres and poor melanoma-specific survival (HR 2.05, 95% CI 1.33-3.16) compared to patients with long telomeres. Due to inverse correlation between age and telomere length (r -0.19, P < 0.0001), we stratified the patients into quantiles based on age at diagnosis and also carried out age-matched analysis. The effect of short telomeres on survival was determined by using multivariate Cox regression that included composite genetic risk score computed from genotyping of the patients for telomere-length associated polymorphisms. The effect of decreased telomere length on poor melanoma-specific survival was particularly strong in patients within the age quantile below 30 years (HR 3.82, 95% CI 1.10-13.30) and between 30-40 years (HR 2.69, 95% CI 1.03-7.03). Our study shows that in contrast to increased melanoma risk associated with increased telomere length, decreased telomere length predicts poor survival in melanoma subgroups.
Collapse
Affiliation(s)
| | - Nalini Srinivas
- Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany
| | - Seyed Hamidreza Mahmoudpour
- Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany
- Institute of Medical Biostatistics, University Medical Center of Johannes Gutenberg, University of Mainz, Mainz, Germany
| | - Zaida Garcia-Casado
- Labortory of Molecular Biology, Instituto Valenciano de Oncologia, Valencia, Spain
| | - Celia Requena
- Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain
| | - Victor Traves
- Department of Pathology, Instituto Valenciano de Oncologia, Valencia, Spain
| | - Virtudes Soriano
- Department of Medical Oncology, Instituto Valenciano de Oncologia, Valencia, Spain
| | - Maurizio Cardelli
- Advanced Technology Center for Aging Research, Italian National Research Center on Aging (INRCA), Ancona, Italy
| | - Dace Pjanova
- Latvian Biomedical Research and Study Centre, Riga, Latvia
| | - Anders Molven
- Department of Clinical Medicine, Gade Laboratory of Pathology, Haukeland University Hospital, Bergen, Norway
- Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Nelleke Gruis
- Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Eduardo Nagore
- Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain
| | - Rajiv Kumar
- Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
- German Consortium for Translational Research, German Cancer Research Center, Heidelberg, Germany.
| |
Collapse
|
|
49
|
Wang Y, Zhou W, Alter BP, Wang T, Spellman SR, Haagenson M, Yeager M, Lee SJ, Chanock SJ, Savage SA, Gadalla SM. Chromosomal Aberrations and Survival after Unrelated Donor Hematopoietic Stem Cell Transplant in Patients with Fanconi Anemia. Biol Blood Marrow Transplant 2018; 24:2003-2008. [PMID: 29879518 DOI: 10.1016/j.bbmt.2018.05.027] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 05/31/2018] [Indexed: 12/11/2022]
Abstract
Studies of chromosomal aberrations in blood or bone marrow of patients with Fanconi anemia (FA) have focused on their associations with leukemic transformation. The role of such abnormalities on outcomes after hematopoietic cell transplantation (HCT) is unclear. We used genome-wide single nucleotide polymorphism arrays to identify chromosomal aberrations in pre-HCT blood samples from 73 patients with FA who received unrelated donor HCT for severe aplastic anemia between 1991 and 2007. Outcome data and blood samples were available through the Center for International Blood and Marrow Transplant Research. For survival analyses, we used the Kaplan-Meier estimator to calculate the survival probabilities and the exact log-rank test to compare the survival differences across groups. Chromosomal aberrations were detected in 16 (22%) patients; most frequent were clonal copy loss in chromosome 7 (9.6%), clonal copy gains in the long arm (q) of chromosome 1 (chr1q+) (8.2%), and clonal or complete copy gains in the q arm of chromosome 3 (chr3q+) (8.2%). Seven (9.6%) patients had alterations in 3 or more chromosomes. Poor post-HCT overall survival (OS) was noted in patients with chr3q+ (P = .04), or those with abnormalities in ≥3 chromosomes (P = .03). The 1-year OS was 0% versus 45% in patients with either alteration versus its absence. No statistically significant differences in OS were noted in patients carrying deletions in chr7 (1-year OS = 29% versus 42%; log-rank P = .74). The study is limited by the small sample size. A larger, prospective study is warranted to validate our findings in light of recent improvement in transplant modalities and outcomes.
Collapse
Affiliation(s)
- Youjin Wang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Weiyin Zhou
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland; Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | - Blanche P Alter
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Tao Wang
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Biostatistics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Stephen R Spellman
- Center for International Blood and Marrow Transplant Research, Minneapolis, Minnesota
| | - Michael Haagenson
- Center for International Blood and Marrow Transplant Research, Minneapolis, Minnesota
| | - Meredith Yeager
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland; Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | - Stephanie J Lee
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Stephen J Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Sharon A Savage
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - Shahinaz M Gadalla
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
| |
Collapse
|
|
50
|
Donor telomere length and causes of death after unrelated hematopoietic cell transplantation in patients with marrow failure. Blood 2018; 131:2393-2398. [PMID: 29632022 DOI: 10.1182/blood-2017-10-812735] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 04/04/2018] [Indexed: 12/20/2022] Open
Abstract
Previous studies have suggested that longer donor leukocyte telomere length (TL) is associated with improved survival after hematopoietic cell transplantation (HCT) in severe aplastic anemia (SAA). This study aimed to determine whether cell-specific lymphocyte TL is associated with certain post-HCT causes of death. We used flow cytometry and fluorescence in situ hybridization to measure TL in donor total lymphocytes and subsets: naïve enriched T cells (CD45RA+CD20-), memory enriched T cells (CD45RA-CD20-), natural killer (NK) fully differentiated T cells (CD45RA+CD57+), and B cells (CD45RA+CD20+). Competing risk survival regression was used for cause-specific death analyses. Clinical data and biospecimens were available from the Center for International Blood and Marrow Transplant Research database and biorepository. The study included 197 patients who underwent unrelated-donor HCT for SAA between 1988 and 2004. The median age at HCT was 15 years (range, 0.5-40 years), and the median follow-up was 5 years (range, <1 month to 20.7 years). Longer donor TL in all cell subsets was associated with lower risk of all-cause mortality (P < .01). In cause-specific mortality analyses, longer TL in B cells (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.46-0.87; P = .006) and possibly NK fully differentiated T cells (HR, 0.7; 95% CI, 0.51 to 0.97; P = .03) was associated with lower risk of infection-related death. Donor TL in other tested lymphocyte subsets was not statistically significantly associated with death resulting from graft-versus-host disease or graft failure (P > .05). However, a trend toward excess risk of graft-versus-host mortality was noted (HR for total lymphocyte TL, 1.26; P = .15). In conclusion, longer donor TL was associated with reduced rate of infection-related deaths after HCT for SAA.
Collapse
|