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Takahashi H, Kojima D, Watanabe M. Therapeutic potential of trained immunity for malignant disease. Immunol Med 2024:1-12. [PMID: 39639550 DOI: 10.1080/25785826.2024.2438426] [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: 06/06/2024] [Accepted: 11/27/2024] [Indexed: 12/07/2024] Open
Abstract
Trained immunity (TI) is functional memory displayed by innate immune cells (IICs). TI facilitates rapid, non-specific responses to pathogens upon secondary challenge. It is driven by immunological signaling and metabolic rewriting via epigenetic alteration, triggered by recognition of certain stimuli. Recently, immune checkpoint inhibitors have come into common use in clinical oncology settings, and genetically engineered cytotoxic T cells comprise a potent cancer treatment strategy. However, the contributions of TI in the tumor microenvironment (TME) are only beginning to be uncovered. Accumulating evidence that various microorganisms and vaccines convey tumoricidal ability suggest that TI may become a useful anti-cancer tool. The expected roles of TI in tumor therapy are the 1) promotion of proinflammatory cytokine section, 2) enhancement of phagocytosis, 3) quick expansion and recruitment of cancer-specific cytotoxic T cells to the TME through neoantigen presentation, 4) reversal of immunosuppression in the TME, and 5) removal of pathogens associated with carcinogenesis or tumor development. Medium- to long-term TI durability may reduce the risk of tumor development. Recent findings on TI usher in new aspirations for cancer treatment.
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Affiliation(s)
- Hiroyuki Takahashi
- Department of Surgery, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka, Japan
| | - Daibo Kojima
- Department of Surgery, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka, Japan
| | - Masato Watanabe
- Department of Surgery, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka, Japan
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2
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Bauvois B, Nguyen-Khac F, Merle-Béral H, Susin SA. CD38/NAD + glycohydrolase and associated antigens in chronic lymphocytic leukaemia: From interconnected signalling pathways to therapeutic strategies. Biochimie 2024; 227:135-151. [PMID: 39009062 DOI: 10.1016/j.biochi.2024.07.006] [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: 06/14/2024] [Accepted: 07/12/2024] [Indexed: 07/17/2024]
Abstract
Chronic lymphocytic leukaemia (CLL) is a heterogenous disease characterized by the accumulation of neoplastic CD5+/CD19+ B lymphocytes. The spreading of the leukaemia relies on the CLL cell's ability to survive in the blood and migrate to and proliferate within the bone marrow and lymphoid tissues. Some patients with CLL are either refractory to the currently available therapies or relapse after treatment; this emphasizes the need for novel therapeutic strategies that improving clinical responses and overcome drug resistance. CD38 is a marker of a poor prognosis and governs a set of survival, proliferation and migration signals that contribute to the pathophysiology of CLL. The literature data evidence a spatiotemporal association between the cell surface expression of CD38 and that of other CLL antigens, such as the B-cell receptor (BCR), CD19, CD26, CD44, the integrin very late antigen 4 (VLA4), the chemokine receptor CXCR4, the vascular endothelial growth factor receptor-2 (VEGF-R2), and the neutrophil gelatinase-associated lipocalin receptor (NGAL-R). Most of these proteins contribute to CLL cell survival, proliferation and trafficking, and cooperate with CD38 in multilayered signal transduction processes. In general, these antigens have already been validated as therapeutic targets in cancer, and a broad repertoire of specific monoclonal antibodies and derivatives are available. Here, we review the state of the art in this field and examine the therapeutic opportunities for cotargeting CD38 and its partners in CLL, e.g. by designing novel bi-/trispecific antibodies.
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MESH Headings
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/immunology
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- ADP-ribosyl Cyclase 1/metabolism
- ADP-ribosyl Cyclase 1/immunology
- Signal Transduction
- Antigens, Neoplasm/immunology
- Antigens, Neoplasm/metabolism
- Membrane Glycoproteins/metabolism
- Membrane Glycoproteins/immunology
- Animals
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Affiliation(s)
- Brigitte Bauvois
- Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Inserm UMRS1138, Drug Resistance in Hematological Malignancies Team, F-75006, Paris, France.
| | - Florence Nguyen-Khac
- Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Inserm UMRS1138, Drug Resistance in Hematological Malignancies Team, F-75006, Paris, France; Sorbonne Université, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, F-75013, Paris, France.
| | - Hélène Merle-Béral
- Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Inserm UMRS1138, Drug Resistance in Hematological Malignancies Team, F-75006, Paris, France.
| | - Santos A Susin
- Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Inserm UMRS1138, Drug Resistance in Hematological Malignancies Team, F-75006, Paris, France.
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Shabani M, Rostamzadeh D, Mansouri M, Jeddi-Tehrani M. Overview on Immunopathology of Chronic Lymphocytic Leukemia and Tumor-Associated Antigens with Therapeutic Applications. Avicenna J Med Biotechnol 2024; 16:201-222. [PMID: 39606680 PMCID: PMC11589431 DOI: 10.18502/ajmb.v16i4.16737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Accepted: 07/20/2024] [Indexed: 11/29/2024] Open
Abstract
Chronic Lymphocytic Leukemia (CLL) is a clinically and biologically heterogeneous disease with a variable clinical course. The induction of a generalized state of immuno-suppression, leading to susceptibility to infections and the failure of anti-tumor immune responses, is a key feature of the clinical course of CLL. In addition to B-cell receptor (BCR) signaling in CLL, several receptor tyrosine kinases (RTKs) have been reported to be constitutively active in leukemic B cells, resulting in promoted survival and resistance to apoptosis induced by chemotherapy. Several treatment options are available for CLL, including a watch-and-wait strategy, chemotherapy, targeted therapies, immunotherapies such as adoptive cellular therapy (CAR T-Cell Therapy), stem cell transplantation (allogeneic transplantation), radiation therapy and surgery. The identification of Tumor-Associated Antigens (TAAs) is the bottleneck of tumor immunology and immunotherapy, serving as promising targets for precise diagnosis, monitoring, or therapeutic approaches. Numerous TAAs have been identified, and their application in immunotherapy holds promise for the treatment of CLL. Furthermore, extensive ongoing research aims to identify new cancer TAAs. In this review, our objective is to provide a comprehensive overview of CLL immunology and recent findings regarding advances in TAAs with therapeutic applications in CLL.
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Affiliation(s)
- Mahdi Shabani
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davoud Rostamzadeh
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Mansoure Mansouri
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahmood Jeddi-Tehrani
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
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4
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Bende RJ, Donner N, Wormhoudt TA, Beentjes A, Scantlebery A, Grobben M, Tejjani K, Chandler F, Sikkema RS, Langerak AW, Guikema JE, van Noesel CJ. Distinct groups of autoantigens as drivers of ocular adnexal MALT lymphoma pathogenesis. Life Sci Alliance 2024; 7:e202402841. [PMID: 38977312 PMCID: PMC11231493 DOI: 10.26508/lsa.202402841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 06/28/2024] [Accepted: 06/28/2024] [Indexed: 07/10/2024] Open
Abstract
Chronic B-cell receptor signals incited by cognate antigens are believed to play a crucial role in the pathogenesis of mucosa-associated lymphoid tissue lymphomas. We have explored the immunoglobulin variable regions (IGHV) expressed by 124 ocular adnexal MALT lymphomas (OAML) and tested the in vitro reactivity of recombinant IgM derived from 23 OAMLs. Six of 124 OAMLs (5%) were found to express a high-affinity stereotyped rheumatoid factor. OAMLs have a biased IGHV4-34 usage, which confers intrinsic super auto-antigen reactivity with poly-N-acetyllactosamine (NAL) epitopes, present on cell surface glycoproteins of erythrocytes and B cells. Twenty-one OAMLs (17%) expressed IGHV4-34-encoded B-cell receptors. Five of the 23 recombinant OAML IgMs expressed IGHV4-34, four of which bound to the linear NAL i epitope expressed on B cells but not to the branched NAL I epitope on erythrocytes. One non-IGHV4-34-encoded OAML IgM was also reactive with B cells. Interestingly, three of the 23 OAML IgMs (13%) specifically reacted with proteins of U1-/U-snRNP complexes, which have been implicated as cognate-antigens in various autoimmune diseases such as systemic lupus erythematosus and mixed connective tissue disease. The findings indicate that local autoimmune reactions are instrumental in the pathogenesis of a substantial fraction of OAMLs.
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MESH Headings
- Humans
- Lymphoma, B-Cell, Marginal Zone/immunology
- Lymphoma, B-Cell, Marginal Zone/genetics
- Autoantigens/immunology
- Immunoglobulin M/immunology
- Immunoglobulin M/metabolism
- Eye Neoplasms/immunology
- Eye Neoplasms/genetics
- Female
- Middle Aged
- Receptors, Antigen, B-Cell/metabolism
- Receptors, Antigen, B-Cell/immunology
- Receptors, Antigen, B-Cell/genetics
- B-Lymphocytes/immunology
- B-Lymphocytes/metabolism
- Male
- Aged
- Immunoglobulin Variable Region/genetics
- Immunoglobulin Variable Region/immunology
- Aged, 80 and over
- Epitopes/immunology
- Adult
- Rheumatoid Factor/immunology
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Affiliation(s)
- Richard J Bende
- Department of Pathology, Amsterdam UMC, Location University of Amsterdam, Amsterdam, Netherlands
- Lymphoma and Myeloma Center (LYMMCARE), Amsterdam, Netherlands
- Cancer Center Amsterdam (CCA), Amsterdam, Netherlands
| | - Naomi Donner
- Department of Pathology, Amsterdam UMC, Location University of Amsterdam, Amsterdam, Netherlands
| | - Thera Am Wormhoudt
- Department of Pathology, Amsterdam UMC, Location University of Amsterdam, Amsterdam, Netherlands
- Lymphoma and Myeloma Center (LYMMCARE), Amsterdam, Netherlands
- Cancer Center Amsterdam (CCA), Amsterdam, Netherlands
| | - Anna Beentjes
- Department of Pathology, Amsterdam UMC, Location University of Amsterdam, Amsterdam, Netherlands
| | - Angelique Scantlebery
- Department of Pathology, Amsterdam UMC, Location University of Amsterdam, Amsterdam, Netherlands
| | - Marloes Grobben
- Department of Medical Microbiology and Infection Prevention, Laboratory of Experimental Virology, Amsterdam UMC, Location University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, Netherlands
| | - Khadija Tejjani
- Department of Medical Microbiology and Infection Prevention, Laboratory of Experimental Virology, Amsterdam UMC, Location University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, Netherlands
| | | | - Reina S Sikkema
- Department of Viroscience, Erasmus MC, Rotterdam, Netherlands
| | - Anton W Langerak
- Department of Immunology, Laboratory Medical Immunology, Erasmus MC, Rotterdam, Netherlands
| | - Jeroen Ej Guikema
- Department of Pathology, Amsterdam UMC, Location University of Amsterdam, Amsterdam, Netherlands
- Lymphoma and Myeloma Center (LYMMCARE), Amsterdam, Netherlands
- Cancer Center Amsterdam (CCA), Amsterdam, Netherlands
| | - Carel Jm van Noesel
- Department of Pathology, Amsterdam UMC, Location University of Amsterdam, Amsterdam, Netherlands
- Lymphoma and Myeloma Center (LYMMCARE), Amsterdam, Netherlands
- Cancer Center Amsterdam (CCA), Amsterdam, Netherlands
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Vuscan P, Kischkel B, Joosten LAB, Netea MG. Trained immunity: General and emerging concepts. Immunol Rev 2024; 323:164-185. [PMID: 38551324 DOI: 10.1111/imr.13326] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 03/11/2024] [Indexed: 05/18/2024]
Abstract
Over the past decade, compelling evidence has unveiled previously overlooked adaptive characteristics of innate immune cells. Beyond their traditional role in providing short, non-specific protection against pathogens, innate immune cells can acquire antigen-agnostic memory, exhibiting increased responsiveness to secondary stimulation. This long-term de-facto innate immune memory, also termed trained immunity, is mediated through extensive metabolic rewiring and epigenetic modifications. While the upregulation of trained immunity proves advantageous in countering immune paralysis, its overactivation contributes to the pathogenesis of autoinflammatory and autoimmune disorders. In this review, we present the latest advancements in the field of innate immune memory followed by a description of the fundamental mechanisms underpinning trained immunity generation and different cell types that mediate it. Furthermore, we explore its implications for various diseases and examine current limitations and its potential therapeutic targeting in immune-related disorders.
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Affiliation(s)
- Patricia Vuscan
- Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Brenda Kischkel
- Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Leo A B Joosten
- Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
- Department for Immunology and Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
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Schmid VK, Hobeika E. B cell receptor signaling and associated pathways in the pathogenesis of chronic lymphocytic leukemia. Front Oncol 2024; 14:1339620. [PMID: 38469232 PMCID: PMC10926848 DOI: 10.3389/fonc.2024.1339620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 02/06/2024] [Indexed: 03/13/2024] Open
Abstract
B cell antigen receptor (BCR) signaling is a key driver of growth and survival in both normal and malignant B cells. Several lines of evidence support an important pathogenic role of the BCR in chronic lymphocytic leukemia (CLL). The significant improvement of CLL patients' survival with the use of various BCR pathway targeting inhibitors, supports a crucial involvement of BCR signaling in the pathogenesis of CLL. Although the treatment landscape of CLL has significantly evolved in recent years, no agent has clearly demonstrated efficacy in patients with treatment-refractory CLL in the long run. To identify new drug targets and mechanisms of drug action in neoplastic B cells, a detailed understanding of the molecular mechanisms of leukemic transformation as well as CLL cell survival is required. In the last decades, studies of genetically modified CLL mouse models in line with CLL patient studies provided a variety of exciting data about BCR and BCR-associated kinases in their role in CLL pathogenesis as well as disease progression. BCR surface expression was identified as a particularly important factor regulating CLL cell survival. Also, BCR-associated kinases were shown to provide a crosstalk of the CLL cells with their tumor microenvironment, which highlights the significance of the cells' milieu in the assessment of disease progression and treatment. In this review, we summarize the major findings of recent CLL mouse as well as patient studies in regard to the BCR signalosome and discuss its relevance in the clinics.
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Affiliation(s)
| | - Elias Hobeika
- Institute of Immunology, Ulm University, Ulm, Germany
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7
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Tetens MM, Omland LH, Dessau R, Ellermann-Eriksen S, Andersen NS, Jørgensen CS, Østergaard C, Bodilsen J, Søgaard KK, Bangsborg J, Nielsen AC, Møller JK, Chen M, Niemann CU, Lebech AM, Obel N. Risk of haematologic cancers among individuals tested for Borrelia burgdorferi antibodies, and Borrelia burgdorferi seropositive individuals: a nationwide population-based matched cohort study. Clin Microbiol Infect 2024; 30:231-239. [PMID: 37871679 DOI: 10.1016/j.cmi.2023.10.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 09/28/2023] [Accepted: 10/16/2023] [Indexed: 10/25/2023]
Abstract
OBJECTIVES In a nationwide, matched cohort study, we aimed to investigate risks of haematologic cancers among individuals tested for Borrelia burgdorferi (Bb) antibodies, and among serum Bb seropositive individuals. METHODS We identified all Bb seropositive individuals in Denmark (1993-2020) (n = 52 200) and constructed two age- and sex-matched comparison cohorts: (a) Bb seronegative controls (n = 104 400) and (b) background population controls (n = 261 000). We calculated short-term OR (aOR) (<1 month of study inclusion), and long-term hazard ratios (aHR) (>1 month after study inclusion) adjusted for age and sex. We stratified seropositive individuals on only Bb-IgM seropositive (n = 26 103), only Bb-IgG seropositive (n = 18 698), and Bb-IgM-and-IgG seropositive (n = 7399). RESULTS Compared with the background population, individuals tested for Bb antibodies had increased short-term (aOR: 12.6, 95% CI: 10.1-15.6) and long-term (aHR: 1.3, 95% CI: 1.2-1.4) risk of haematologic cancers. The Bb seropositive individuals had no increased risk of haematologic cancers compared with those who tested negative for Bb, except that Bb-IgM-and-IgG seropositive individuals had increased long-term risk of chronic lymphatic leukaemia (aHR: 2.0, 95% CI: 1.2-3.4). DISCUSSION Our results suggest that Bb antibody testing is included in the work-up of unspecific symptoms preceding diagnosis of haematologic cancers. Bb-IgM-and-IgG seropositivity was associated with a two-fold increased long-term risk of chronic lymphatic leukaemia, which warrants further investigation.
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Affiliation(s)
- Malte M Tetens
- Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
| | - Lars Haukali Omland
- Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Ram Dessau
- Department of Clinical Microbiology, Zealand Hospital, Slagelse, Denmark; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
| | | | - Nanna S Andersen
- Clinical Centre for Emerging and Vector-borne Infections, Department of Clinical Microbiology, Odense University Hospital, Odense, Denmark; Research Unit of Clinical Microbiology, University of Southern Denmark, Odense, Denmark
| | | | - Christian Østergaard
- Department of Clinical Microbiology, Copenhagen University Hospital - Hvidovre Hospital, Copenhagen, Denmark
| | - Jacob Bodilsen
- Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Kirstine K Søgaard
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; Department of Clinical Microbiology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
| | - Jette Bangsborg
- Department of Clinical Microbiology, Copenhagen University Hospital - Herlev Hospital, Herlev, Denmark
| | - Alex Christian Nielsen
- Department of Clinical Microbiology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Jens Kjølseth Møller
- Department of Regional Health Research, University of Southern Denmark, Odense, Denmark; Department of Clinical Microbiology, Vejle Hospital, University Hospital of Southern Denmark, Vejle, Denmark
| | - Ming Chen
- Department of Clinical Microbiology, Sønderborg Hospital, Sønderborg, Denmark
| | - Carsten Utoft Niemann
- Department of Hematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Anne-Mette Lebech
- Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Niels Obel
- Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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8
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Rodríguez-García A, Mennesson N, Hernandez-Ibarburu G, Morales ML, Garderet L, Bouchereau L, Allain-Maillet S, Piver E, Marbán I, Rubio D, Bigot-Corbel E, Martínez-López J, Linares M, Hermouet S. Impact of viral hepatitis therapy in multiple myeloma and other monoclonal gammopathies linked to hepatitis B or C viruses. Haematologica 2024; 109:272-282. [PMID: 37199121 PMCID: PMC10772493 DOI: 10.3324/haematol.2023.283096] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 05/10/2023] [Indexed: 05/19/2023] Open
Abstract
Subsets of multiple myeloma (MM) and monoclonal gammopathies of undetermined significance (MGUS) present with a monoclonal immunoglobulin specific for hepatitis C virus (HCV), thus are presumably HCV-driven, and antiviral treatment can lead to the disappearance of antigen stimulation and improved control of clonal plasma cells. Here we studied the role of hepatitis B virus (HBV) in the pathogenesis of MGUS and MM in 45 HBV-infected patients with monoclonal gammopathy. We analyzed the specificity of recognition of the monoclonal immunoglobulin of these patients and validated the efficacy of antiviral treatment (AVT). For 18 of 45 (40%) HBV-infected patients, the target of the monoclonal immunoglobulin was identified: the most frequent target was HBV (n=11), followed by other infectious pathogens (n=6) and glucosylsphingosine (n=1). Two patients whose monoclonal immunoglobulin targeted HBV (HBx and HBcAg), implying that their gammopathy was HBV-driven, received AVT and the gammopathy did not progress. AVT efficacy was then investigated in a large cohort of HBV-infected MM patients (n=1367) who received or did not receive anti-HBV treatments and compared to a cohort of HCV-infected MM patients (n=1220). AVT significantly improved patient probability of overall survival (P=0.016 for the HBV-positive cohort, P=0.005 for the HCV-positive cohort). Altogether, MGUS and MM disease can be HBV- or HCV-driven in infected patients, and the study demonstrates the importance of AVT in such patients.
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Affiliation(s)
- Alba Rodríguez-García
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (i+12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, ES 28041, Madrid
| | - Nicolas Mennesson
- Nantes Université, INSERM, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302, F-44000 Nantes
| | - Gema Hernandez-Ibarburu
- Biomedical Informatics Group, Universidad Politécnica de Madrid, Madrid, Spain; TriNetX LLC, Madrid
| | - María Luz Morales
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (i+12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, ES 28041, Madrid
| | - Laurent Garderet
- Sorbonne Université-INSERM, UMR_S 938, Centre de Recherche Saint-Antoine-Team Hematopoietic and leukemic development, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpetrière, Département d'Hématologie et de Thérapie Cellulaire, F-75013 Paris
| | - Lorine Bouchereau
- Nantes Université, INSERM, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302, F-44000 Nantes
| | - Sophie Allain-Maillet
- Nantes Université, INSERM, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302, F-44000 Nantes
| | - Eric Piver
- Laboratoire de Biochimie, CHU Tours, Tours, France; Inserm UMR1253, MAVIVH Tours
| | - Irene Marbán
- Biomedical Informatics Group, Universidad Politécnica de Madrid, Madrid
| | - David Rubio
- Biomedical Informatics Group, Universidad Politécnica de Madrid, Madrid, Spain; TriNetX LLC, Madrid
| | - Edith Bigot-Corbel
- Nantes Université, INSERM, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302, F-44000 Nantes, France; Laboratoire de Biochimie, CHU Nantes, F-44000, Nantes
| | - Joaquín Martínez-López
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (i+12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, ES 28041, Madrid, Spain; Department of Medicine, Medicine School, Universidad Complutense de Madrid, ES 28040, Madrid
| | - María Linares
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (i+12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, ES 28041, Madrid, Spain; Department of Biochemistry and Molecular Biology, Pharmacy School, Universidad Complutense de Madrid, ES 28040, Madrid.
| | - Sylvie Hermouet
- Nantes Université, INSERM, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302, F-44000 Nantes, France; Laboratoire d'Hématologie, CHU Nantes, F-44000, Nantes.
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9
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Hermouet S, Bigot-Corbel E, Harb J. Determination of the target of monoclonal immunoglobulins: a novel diagnostic tool for individualized MGUS therapy, and prevention and therapy of smoldering and multiple myeloma. Front Immunol 2023; 14:1253363. [PMID: 38022528 PMCID: PMC10644846 DOI: 10.3389/fimmu.2023.1253363] [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: 07/05/2023] [Accepted: 09/11/2023] [Indexed: 12/01/2023] Open
Abstract
Subsets of patients diagnosed with a monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) or multiple myeloma (MM), present with a monoclonal immunoglobulin (Ig) specific for an infectious pathogen, including hepatitis C and B viruses (HCV, HBV), Helicobacter pylori and several Herpesviruses. Such cases are likely initiated by infection, since in the context of HCV- or HBV-infected patients, antiviral therapy can lead to the disappearance of antigenic stimulation, control of clonal plasma cells, and reduced or suppressed monoclonal Ig production. Complete remission has been obtained with anti-HCV therapy in refractory MM with a HCV-specific monoclonal Ig, and antiviral treatments significantly improved the probability of survival of MM patients infected with HCV or HBV prior to the diagnosis of MM. Monoclonal Igs may also target glucolipids, particularly glucosylsphingosine (GlcSph), and GlcSph-reducing therapy can lead to complete remission in SMM and MM patients presenting with a GlcSph-specific monoclonal Ig. The present review describes the importance of determining the target of the monoclonal Ig of MGUS, SMM and MM patients, and discusses the efficacy of target-reducing treatments in the management of MGUS, SMM and MM cases who present with a monoclonal Ig reactive against a treatable infectious pathogen or GlcSph.
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Affiliation(s)
- Sylvie Hermouet
- Nantes Université, INSERM, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302, Nantes, France
- Laboratoire d’Hématologie, CHU Nantes, Nantes, France
| | - Edith Bigot-Corbel
- Nantes Université, INSERM, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302, Nantes, France
- Laboratoire de Biochimie, CHU Nantes, Nantes, France
| | - Jean Harb
- Laboratoire de Biochimie, CHU Nantes, Nantes, France
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10
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Koehrer S, Burger JA. Chronic Lymphocytic Leukemia: Disease Biology. Acta Haematol 2023; 147:8-21. [PMID: 37717577 PMCID: PMC11753505 DOI: 10.1159/000533610] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 08/13/2023] [Indexed: 09/19/2023]
Abstract
BACKGROUND B-cell receptor (BCR) signaling is crucial for normal B-cell development and adaptive immunity. In chronic lymphocytic leukemia (CLL), the malignant B cells display many features of normal mature B lymphocytes, including the expression of functional B-cell receptors (BCRs). Cross talk between CLL cells and the microenvironment in secondary lymphatic organs results in BCR signaling and BCR-driven proliferation of the CLL cells. This critical pathomechanism can be targeted by blocking BCR-related kinases (BTK, PI3K, spleen tyrosine kinase) using small-molecule inhibitors. Among these targets, Bruton tyrosine kinase (BTK) inhibitors have the highest therapeutic efficacy; they effectively block leukemia cell proliferation and generally induce durable remissions in CLL patients, even in patients with high-risk disease. By disrupting tissue homing receptor (i.e., chemokine receptor and adhesion molecule) signaling, these kinase inhibitors also mobilize CLL cells from the lymphatic tissues into the peripheral blood (PB), causing a transient redistribution lymphocytosis, thereby depriving CLL cells from nurturing factors within the tissue niches. SUMMARY The clinical success of the BTK inhibitors in CLL underscores the central importance of the BCR in CLL pathogenesis. Here, we review CLL pathogenesis with a focus on the role of the BCR and other microenvironment cues. KEY MESSAGES (i) CLL cells rely on signals from their microenvironment for proliferation and survival. (ii) These signals are mediated by the BCR as well as chemokine and integrin receptors and their respective ligands. (iii) Targeting the CLL/microenvironment interaction with small-molecule inhibitors provides a highly effective treatment strategy, even in high-risk patients.
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Affiliation(s)
- Stefan Koehrer
- Department of Laboratory Medicine, Klinik Donaustadt, Vienna, Austria
- Labdia Labordiagnostik, Clinical Genetics, Vienna, Austria
- St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
| | - Jan A. Burger
- Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA
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Witkowska M, Majchrzak A, Robak P, Wolska-Washer A, Robak T. Metabolic and toxicological considerations for phosphoinositide 3-kinase delta inhibitors in the treatment of chronic lymphocytic leukemia. Expert Opin Drug Metab Toxicol 2023; 19:617-633. [PMID: 37714711 DOI: 10.1080/17425255.2023.2260305] [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: 06/02/2023] [Revised: 08/22/2023] [Accepted: 09/14/2023] [Indexed: 09/17/2023]
Abstract
INTRODUCTION Phosphoinositide 3-kinase delta (PI3Kδ) inhibitors are a class of novel agents that are mainly used to treat B-cell malignancies. They function by inhibiting one or more enzymes which are part of the PI3K/AKT/mTOR pathway. Idelalisib is a first-in-class PI3Kδ inhibitor effective in patients with B-cell lymphoid malignancies. AREAS COVERED This article reviews the chemical structure, mechanism of action, and metabolic and toxicological properties of PI3Kδ inhibitors and discusses their clinical applications in monotherapy and in combination with other agents for the treatment of chronic lymphocytic leukemia (CLL). A search was conducted of PubMed, Web of Science, and Google Scholar for articles in English. RESULTS/CONCLUSION PI3Kδ inhibitors hold potential for the treatment of B-cell malignancies, including CLL. However, their use is also associated with severe toxicities, including pneumonia, cytopenias, hepatitis, and rash. Newer drugs are in development to reduce toxicity with novel schedules and/or combinations. EXPERT OPINION The development of novel PI3Kδ inhibitors might help to reduce toxicity and improve efficacy in patients with CLL and other B-cell lymphoid malignancies.
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Affiliation(s)
- Magdalena Witkowska
- Department of Experimental Hematology, Medical University of Lodz, Lodz, Poland
- Department of Hematooncology, Copernicus Memorial Hospital, Lodz, Poland
| | - Agata Majchrzak
- Department of General Hematology, Copernicus Memorial Hospital, Lodz, Poland
| | - Paweł Robak
- Department of Experimental Hematology, Medical University of Lodz, Lodz, Poland
- Department of Hematooncology, Copernicus Memorial Hospital, Lodz, Poland
| | - Anna Wolska-Washer
- Department of Experimental Hematology, Medical University of Lodz, Lodz, Poland
- Department of Hematooncology, Copernicus Memorial Hospital, Lodz, Poland
| | - Tadeusz Robak
- Department of General Hematology, Copernicus Memorial Hospital, Lodz, Poland
- Department of Hematology, Medical University of Lodz, Lodz, Poland
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12
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Wang J, Lundström SL, Lu W, Huang Y, Rodin S, Zubarev RA. SpotLight proteomics identifies variable sequences of blood antibodies specific against deamidated human serum albumin. Mol Cell Proteomics 2023:100589. [PMID: 37301377 PMCID: PMC10345337 DOI: 10.1016/j.mcpro.2023.100589] [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: 01/15/2023] [Revised: 05/23/2023] [Accepted: 06/07/2023] [Indexed: 06/12/2023] Open
Abstract
Spontaneous deamidation of asparaginyl residues in proteins, if not repaired or cleared, can set in motion a cascade that leads to deteriorated health. Previously, we have discovered that deamidated human serum albumin (HSA) is elevated in blood of patients with Alzheimer's disease and other neurodegenerative diseases, while the level of endogenous antibodies against deamidated HSA is significantly diminished, creating an imbalance between the risk factor and the defense against it. Endogenous antibodies against deamidated proteins are still unexplored. In the current study, we employed the SpotLight proteomics approach to identify novel amino acid sequences in antibodies specific to deamidated HSA. The results provide new insights into the clearance mechanism of deamidated proteins, a possible avenue for prevention of neurodegeneration.
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Affiliation(s)
- Jijing Wang
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17 165 Stockholm, Sweden
| | - Susanna L Lundström
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17 165 Stockholm, Sweden
| | - Weiqi Lu
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17 165 Stockholm, Sweden; Department of Ophthalmology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yiqi Huang
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17 165 Stockholm, Sweden; Institute of Virology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Sergey Rodin
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17 165 Stockholm, Sweden; Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Roman A Zubarev
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17 165 Stockholm, Sweden.
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Coyne V, Mead HL, Mongini PKA, Barker BM. B Cell Chronic Lymphocytic Leukemia Development in Mice with Chronic Lung Exposure to Coccidioides Fungal Arthroconidia. Immunohorizons 2023; 7:333-352. [PMID: 37195872 PMCID: PMC10579974 DOI: 10.4049/immunohorizons.2300013] [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: 03/01/2023] [Accepted: 04/24/2023] [Indexed: 05/19/2023] Open
Abstract
Links between repeated microbial infections and B cell chronic lymphocytic leukemia (B-CLL) have been proposed but not tested directly. This study examines how prolonged exposure to a human fungal pathogen impacts B-CLL development in Eµ-hTCL1-transgenic mice. Monthly lung exposure to inactivated Coccidioides arthroconidia, agents of Valley fever, altered leukemia development in a species-specific manner, with Coccidioides posadasii hastening B-CLL diagnosis/progression in a fraction of mice and Coccidioides immitis delaying aggressive B-CLL development, despite fostering more rapid monoclonal B cell lymphocytosis. Overall survival did not differ significantly between control and C. posadasii-treated cohorts but was significantly extended in C. immitis-exposed mice. In vivo doubling time analyses of pooled B-CLL showed no difference in growth rates of early and late leukemias. However, within C. immitis-treated mice, B-CLL manifests longer doubling times, as compared with B-CLL in control or C. posadasii-treated mice, and/or evidence of clonal contraction over time. Through linear regression, positive relationships were noted between circulating levels of CD5+/B220low B cells and hematopoietic cells previously linked to B-CLL growth, albeit in a cohort-specific manner. Neutrophils were positively linked to accelerated growth in mice exposed to either Coccidioides species, but not in control mice. Conversely, only C. posadasii-exposed and control cohorts displayed positive links between CD5+/B220low B cell frequency and abundance of M2 anti-inflammatory monocytes and T cells. The current study provides evidence that chronic lung exposure to fungal arthroconidia affects B-CLL development in a manner dependent on fungal genotype. Correlative studies suggest that fungal species differences in the modulation of nonleukemic hematopoietic cells are involved.
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Affiliation(s)
- Vanessa Coyne
- Pathogen Microbiome Institute, Northern Arizona University, Flagstaff, AZ
| | - Heather L. Mead
- Pathogen Microbiome Institute, Northern Arizona University, Flagstaff, AZ
| | | | - Bridget M. Barker
- Pathogen Microbiome Institute, Northern Arizona University, Flagstaff, AZ
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Najmi A, Thangavel N, Mohanan AT, Qadri M, Albratty M, Ashraf SE, Saleh SF, Nayeem M, Mohan S. Structural Complementarity of Bruton’s Tyrosine Kinase and Its Inhibitors for Implication in B-Cell Malignancies and Autoimmune Diseases. Pharmaceuticals (Basel) 2023; 16:ph16030400. [PMID: 36986499 PMCID: PMC10051736 DOI: 10.3390/ph16030400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/08/2023] [Accepted: 02/24/2023] [Indexed: 03/09/2023] Open
Abstract
Bruton’s tyrosine kinase (BTK) is a critical component in B-cell receptor (BCR) signaling and is also expressed in haematogenic and innate immune cells. Inhibition of BTK hyperactivity is implicated in B-cell malignancies and autoimmune diseases. This review derives the structural complementarity of the BTK-kinase domain and its inhibitors from recent three-dimensional structures of inhibitor-bound BTK in the protein data bank (PDB). Additionally, this review analyzes BTK-mediated effector responses of B-cell development and antibody production. Covalent inhibitors contain an α, β-unsaturated carbonyl moiety that forms a covalent bond with Cys481, stabilizing αC-helix in inactive-out conformation which inhibits Tyr551 autophosphorylation. Asn484, located two carbons far from Cys481, influences the stability of the BTK-transition complex. Non-covalent inhibitors engage the BTK-kinase domain through an induced-fit mechanism independent of Cys481 interaction and bind to Tyr551 in the activation kink resulting in H3 cleft, determining BTK selectivity. Covalent and non-covalent binding to the kinase domain of BTK shall induce conformational changes in other domains; therefore, investigating the whole-length BTK conformation is necessary to comprehend BTK’s autophosphorylation inhibition. Knowledge about the structural complementarity of BTK and its inhibitors supports the optimization of existing drugs and the discovery of drugs for implication in B-cell malignancies and autoimmune diseases.
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Affiliation(s)
- Asim Najmi
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia
| | - Neelaveni Thangavel
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia
- Correspondence: (N.T.); (S.M.)
| | | | - Marwa Qadri
- Department of Pharmacology, College of Pharmacy, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia
| | - Mohammed Albratty
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia
- Medical Research Center, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia
| | - Safeena Eranhiyil Ashraf
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia
| | - Safaa Fathy Saleh
- Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia
| | - Maryam Nayeem
- Department of Pharmacology, College of Pharmacy, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia
| | - Syam Mohan
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Fayoum University, Fayoum 63514, Egypt
- Substance Abuse and Research Centre, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia
- School of Health Sciences, University of Petroleum and Energy Studies, Dehradun 248007, India
- Correspondence: (N.T.); (S.M.)
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Mazzarello AN, Koroveshi B, Guardo D, Lanza L, Ghiotto F, Bruno S, Cappelli E. Unexpected CD5 + B Cell Lymphocytosis during SARS-CoV-2 Infection: Relevance for the Pathophysiology of Chronic Lymphocytic Leukemia. J Clin Med 2023; 12:jcm12030998. [PMID: 36769644 PMCID: PMC9918123 DOI: 10.3390/jcm12030998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 01/17/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023] Open
Abstract
Recently, cases of fortuitous discovery of Chronic Lymphocytic Leukemia (CLL) during hospitalization for Coronavirus disease (COVID-19) have been reported. These patients did not show a monoclonal B cell expansion before COVID-19 but were diagnosed with CLL upon a sudden lymphocytosis that occurred during hospitalization. The (hyper)lymphocytosis during COVID-19 was also described in patients with overt CLL disease. Contextually, lymphocytosis is an unexpected phenomenon since it is an uncommon feature in the COVID-19 patient population, who rather tend to experience lymphopenia. Thus, lymphocytosis that arises during COVID-19 infection is a thought-provoking behavior, strikingly in contrast with that observed in non-CLL individuals. Herein, we speculate about the possible mechanisms involved with the observed phenomenon. Many of the plausible explanations might have an adverse impact on these CLL patients and further clinical and laboratory investigations might be desirable.
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Affiliation(s)
| | - Brisejda Koroveshi
- Laboratory of Clinical Pathology, ASL2 Liguria, S. Paolo Hospital, 17100 Savona, Italy
| | - Daniela Guardo
- Haematology Unit, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16148 Genova, Italy
| | - Lorella Lanza
- Anatomical Pathology, ASL2 Liguria, Santa Corona Hospital, 17027 Pietra Ligure, Italy
| | - Fabio Ghiotto
- Department of Experimental Medicine, University of Genoa, Via De Toni 14, 16132 Genova, Italy
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Silvia Bruno
- Department of Experimental Medicine, University of Genoa, Via De Toni 14, 16132 Genova, Italy
| | - Enrico Cappelli
- Haematology Unit, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16148 Genova, Italy
- Correspondence:
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Old and New Facts and Speculations on the Role of the B Cell Receptor in the Origin of Chronic Lymphocytic Leukemia. Int J Mol Sci 2022; 23:ijms232214249. [PMID: 36430731 PMCID: PMC9693457 DOI: 10.3390/ijms232214249] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/09/2022] [Accepted: 11/11/2022] [Indexed: 11/19/2022] Open
Abstract
The engagement of the B cell receptor (BcR) on the surface of leukemic cells represents a key event in chronic lymphocytic leukemia (CLL) since it can lead to the maintenance and expansion of the neoplastic clone. This notion was initially suggested by observations of the CLL BcR repertoire and of correlations existing between certain BcR features and the clinical outcomes of single patients. Based on these observations, tyrosine kinase inhibitors (TKIs), which block BcR signaling, have been introduced in therapy with the aim of inhibiting CLL cell clonal expansion and of controlling the disease. Indeed, the impressive results obtained with these compounds provided further proof of the role of BcR in CLL. In this article, the key steps that led to the determination of the role of BcR are reviewed, including the features of the CLL cell repertoire and the fine mechanisms causing BcR engagement and cell signaling. Furthermore, we discuss the biological effects of the engagement, which can lead to cell survival/proliferation or apoptosis depending on certain intrinsic cell characteristics and on signals that the micro-environment can deliver to the leukemic cells. In addition, consideration is given to alternative mechanisms promoting cell proliferation in the absence of BcR signaling, which can explain in part the incomplete effectiveness of TKI therapies. The role of the BcR in determining clonal evolution and disease progression is also described. Finally, we discuss possible models to explain the selection of a special BcR set during leukemogenesis. The BcR may deliver activation signals to the cells, which lead to their uncontrolled growth, with the possible collaboration of other still-undefined events which are capable of deregulating the normal physiological response of B cells to BcR-delivered stimuli.
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Al-Mansour M. Treatment Landscape of Relapsed/Refractory Mantle Cell Lymphoma: An Updated Review. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2022; 22:e1019-e1031. [PMID: 36068158 DOI: 10.1016/j.clml.2022.07.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/22/2022] [Accepted: 07/29/2022] [Indexed: 06/15/2023]
Abstract
Mantle cell lymphoma (MCL) accounts for nearly 2-6% of all non-Hodgkin lymphoma (NHL) cases, with a steady incidence increase over the past few decades. Although many patients achieve an adequate response to the upfront treatment, the short duration of remission with rapid relapse is challenging during MCL management. In this regard, there is no consensus on the best treatment options for relapsed/refractory (R/R) disease, and the international guidelines demonstrate wide variations in the recommended approaches. The last decade has witnessed the introduction of new agents in the treatment landscape of R/R MCL. Since the introduction of Bruton's tyrosine kinase (BTK) inhibitors, the treatment algorithm and response of R/R MCL patients have dramatically changed. Nevertheless, BTK resistance is common, necessitating further investigations to develop novel agents with a more durable response. Novel agents targeting the B-cell receptor (BCR) signaling have exhibited clinical activity and a well-tolerable safety profile. However, as the responses to these novel agents are still modest in most clinical trials, combination strategies were investigated in pre-clinical and early clinical settings to determine whether the combination of novel agents would exhibit a better durable response than single agents. In this report, we provide an updated literature review that covers recent clinical data about the safety and efficacy of novel therapies for the management of R/R MCL.
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Affiliation(s)
- Mubarak Al-Mansour
- Adult Medical Oncology, Princess Noorah Oncology Center, Jeddah, Saudi Arabia; College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.
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Sun XY, Yang XD, Yang XQ, Ju B, Xiu NN, Xu J, Zhao XC. Antibiotic and glucocorticoid-induced recapitulated hematological remission in acute myeloid leukemia: A case report and review of literature. World J Clin Cases 2022; 10:7890-7898. [PMID: 36158489 PMCID: PMC9372864 DOI: 10.12998/wjcc.v10.i22.7890] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 10/29/2021] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Leukemic hematopoietic cells acquire enhanced self-renewal capacity and impaired differentiation. The emergence of symptomatic leukemia also requires the acquisition of a clonal proliferative advantage. Untreated leukemia patients usually experience an aggressive process. However, spontaneous remission occasionally occurs in patients with acute myeloid leukemia (AML), most frequently after recovery from a febrile episode, and this is generally attributed to the triggering of antineoplastic immunity. There may be another explanation for the spontaneous remission as implicated in this paper.
CASE SUMMARY A 63-year-old Chinese man presented with high fever, abdominal pain and urticaria-like skin lesions. He was diagnosed with AML-M4 with t(8;21) (q22;q22)/RUNX1-RUNX1T1 based on morphological, immunological, cytogenetic and molecular analyses. He had a complex chromosome rea-rrangement of 48,XY,t(8;21)(q22;q22),+13,+13[9]/49,idem,+mar[9]/49,idem,+8[2]. He also had a mutated tyrosine kinase domain in fms-like tyrosine kinase 3 gene. He was treated with antibiotics and glucocorticoids for gastrointestinal infection and urticaria-like skin lesions. The infection and skin lesions were quickly resolved. Unexpectedly, he achieved hematological remission along with resolution of the febrile episode, gastrointestinal symptoms and skin lesions. Notably, after relapse, repeating these treatments resulted in a return to hematological remission. Unfortunately, he demonstrated strong resistance to antibiotic and glucocorticoid treatment after the second relapse and died of sepsis from bacterial infection with multidrug resistance. The main clinical feature of this patient was that symptomatic AML emerged with flaring of the gut inflammatory disorder and it subsided after resolution of the inflammation. Learning from the present case raises the possibility that in a subgroup of AML patients, the proliferative advantage of leukemia cells may critically require the presence of inflammatory stresses.
CONCLUSION Inflammatory stresses, most likely arising from gastrointestinal infection, may sustain the growth and survival advantage of leukemic cells.
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Affiliation(s)
- Xiao-Yun Sun
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Xiao-Dong Yang
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Xiao-Qiu Yang
- Department of Pharmacology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Bo Ju
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Nuan-Nuan Xiu
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Jia Xu
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Xi-Chen Zhao
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
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Linares M, Hermouet S. Editorial: The Role of Microorganisms in Multiple Myeloma. Front Immunol 2022; 13:960829. [PMID: 35844583 PMCID: PMC9281403 DOI: 10.3389/fimmu.2022.960829] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 06/13/2022] [Indexed: 11/13/2022] Open
Affiliation(s)
- Maria Linares
- Pharmacy School, Universidad Complutense de Madrid, Madrid, Spain
- Department of Translational Haematology, Hospital 12 de Octubre de Madrid, Madrid, Spain
- Laboratory of Haematological Tumours, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
- *Correspondence: Maria Linares,
| | - Sylvie Hermouet
- Nantes Université, INSERM, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302, Nantes, France
- Laboratoire d’Hématologie, Centre Hospitalier Universitaire de Nantes (CHU Nantes), Nantes, France
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Chang LY, Liang SY, Lu SC, Tseng HC, Tsai HY, Tang CJ, Sugata M, Chen YJ, Chen YJ, Wu SJ, Lin KI, Khoo KH, Angata T. Molecular Basis and Role of Siglec-7 Ligand Expression on Chronic Lymphocytic Leukemia B Cells. Front Immunol 2022; 13:840388. [PMID: 35711441 PMCID: PMC9195294 DOI: 10.3389/fimmu.2022.840388] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 04/27/2022] [Indexed: 11/13/2022] Open
Abstract
Siglec-7 (sialic acid-binding immunoglobulin-like lectin 7) is an immune checkpoint-like glycan recognition protein on natural killer (NK) cells. Cancer cells often upregulate Siglec ligands to subvert immunosurveillance, but the molecular basis of Siglec ligands has been elusive. In this study, we investigated Siglec-7 ligands on chronic lymphocytic leukemia (CLL) B cells. CLL B cells express higher levels of Siglec-7 ligands compared with healthy donor B cells, and enzymatic removal of sialic acids or sialomucins makes them more sensitive to NK cell cytotoxicity. Gene knockout experiments have revealed that the sialyltransferase ST6GalNAc-IV is responsible for the biosynthesis of disialyl-T (Neu5Acα2-3Galβ1-3[Neu5Acα2-6]GalNAcα1-), which is the glycotope recognized by Siglec-7, and that CD162 and CD45 are the major carriers of this glycotope on CLL B cells. Analysis of public transcriptomic datasets indicated that the low expression of GCNT1 (encoding core 2 GlcNAc transferase, an enzyme that competes against ST6GalNAc-IV) and high expression of ST6GALNAC4 (encoding ST6GalNAc-IV) in CLL B cells, together enhancing the expression of the disialyl-T glycotope, are associated with poor patient prognosis. Taken together, our results determined the molecular basis of Siglec-7 ligand overexpression that protects CLL B cells from NK cell cytotoxicity and identified disialyl-T as a potential prognostic marker of CLL.
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Affiliation(s)
- Lan-Yi Chang
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Suh-Yuen Liang
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Shao-Chia Lu
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Huan Chuan Tseng
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Ho-Yang Tsai
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
- Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan
| | - Chin-Ju Tang
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Marcelia Sugata
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Yi-Ju Chen
- Institute of Chemistry, Academia Sinica, Taipei, Taiwan
| | - Yu-Ju Chen
- Institute of Chemistry, Academia Sinica, Taipei, Taiwan
| | - Shang-Ju Wu
- Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Kuo-I Lin
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Kay-Hooi Khoo
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
- Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan
| | - Takashi Angata
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
- Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan
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Minton AR, Smith LD, Bryant DJ, Strefford JC, Forconi F, Stevenson FK, Tumbarello DA, James E, Løset GÅ, Munthe LA, Steele AJ, Packham G. B-cell receptor dependent phagocytosis and presentation of particulate antigen by chronic lymphocytic leukemia cells. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:37-49. [PMID: 35309250 PMCID: PMC7612515 DOI: 10.37349/etat.2022.00070] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 01/28/2022] [Indexed: 11/28/2022] Open
Abstract
Aim T-helper cells could play an important role in the pathogenesis of chronic lymphocytic leukemia (CLL), a common B-cell neoplasm. Although CLL cells can present soluble antigens targeted from the B-cell receptor to T-helper cells via major histocompatibility complex (MHC) class II, antigens recognized by some CLL cells may be encountered in a particulate form. Here the ability of CLL cells to internalize and present anti-immunoglobulin M (IgM) beads as a model for the interaction of CLL cells with particulate antigens was investigated. Methods The effect of anti-IgM beads on antigen presentation pathways was analyzed using RNA-seq and internalization of anti-IgM beads by primary CLL cells was investigated using confocal microscopy and flow cytometry. Antigen presentation was investigated by analyzing activation of a T-cell line expressing a T-cell receptor specific for a peptide derived from mouse κ light chains after incubating CLL cells with a mouse κ light chain-containing anti-IgM monoclonal antibody. Kinase inhibitors were used to characterize the pathways mediating internalization and antigen presentation. Results Stimulation of surface IgM of CLL cells increased expression of the antigen presentation machinery and CLL cells were able to phagocytose anti-IgM beads. Internalization of anti-IgM beads was associated with MHC class II-restricted activation of cognate T-helper cells. Antigen presentation by CLL cells was dependent on activity of spleen tyrosine kinase (SYK) and phosphatidylinositol 3-kinase delta (PI3Kδ) but was unaffected by inhibitors of Bruton's tyrosine kinase (BTK). Conclusions CLL cells can internalize and present antigen from anti-IgM beads. This capacity of CLL cells may be particularly important for recruitment of T-cell help in vivo in response to particulate antigens.
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Affiliation(s)
- Annabel R. Minton
- Cancer Research UK Centre, Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
| | - Lindsay D. Smith
- Cancer Research UK Centre, Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
- Current address: Ploughshare Innovations Limited, Porton Science Park, Porton Down, SP4 0BF Wiltshire, UK
| | - Dean J. Bryant
- Cancer Research UK Centre, Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
| | - Jonathan C. Strefford
- Cancer Research UK Centre, Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
| | - Francesco Forconi
- Cancer Research UK Centre, Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
| | - Freda K. Stevenson
- Cancer Research UK Centre, Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
| | - David A. Tumbarello
- Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, SO17 1BJ Southampton, UK
| | - Edd James
- Cancer Research UK Centre, Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
| | | | - Ludvig A. Munthe
- KG Jebsen Centre for B cell Malignancies, Institute of Clinical Medicine, University of Oslo, NO-0424 Oslo, Norway
| | - Andrew J. Steele
- Cancer Research UK Centre, Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
- Current address: Janssen R&D, 1400 McKean Road, Spring House, Ambler, PA 19477, USA
| | - Graham Packham
- Cancer Research UK Centre, Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK
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22
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Rodríguez-García A, Linares M, Morales ML, Allain-Maillet S, Mennesson N, Sanchez R, Alonso R, Leivas A, Pérez-Rivilla A, Bigot-Corbel E, Hermouet S, Martínez-López J. Efficacy of Antiviral Treatment in Hepatitis C Virus (HCV)-Driven Monoclonal Gammopathies Including Myeloma. Front Immunol 2022; 12:797209. [PMID: 35087522 PMCID: PMC8786723 DOI: 10.3389/fimmu.2021.797209] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 12/14/2021] [Indexed: 12/20/2022] Open
Abstract
Multiple myeloma (MM) remains an incurable plasma cell malignancy. While its origin is enigmatic, an association with infectious pathogens including hepatitis C virus (HCV) has been suggested. Here we report nine patients with monoclonal gammopathy of undetermined significance (MGUS) or MM with previous HCV infection, six of whom received antiviral treatment. We studied the evolution of the gammopathy disease, according to anti-HCV treatment and antigen specificity of purified monoclonal immunoglobulin, determined using the INNO-LIA™ HCV Score assay, dot-blot assays, and a multiplex infectious antigen microarray. The monoclonal immunoglobulin from 6/9 patients reacted against HCV. Four of these patients received antiviral treatment and had a better evolution than untreated patients. Following antiviral treatment, one patient with MM in third relapse achieved complete remission with minimal residual disease negativity. For two patients who did not receive antiviral treatment, disease progressed. For the two patients whose monoclonal immunoglobulin did not react against HCV, antiviral treatment was not effective for MGUS or MM disease. Our results suggest a causal relationship between HCV infection and MGUS and MM progression. When HCV was eliminated, chronic antigen-stimulation disappeared, allowing control of clonal plasma cells. This opens new possibilities of treatment for MGUS and myeloma.
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Affiliation(s)
- Alba Rodríguez-García
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, Madrid, Spain
| | - María Linares
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, Madrid, Spain
- Department of Biochemistry and Molecular Biology, Pharmacy School, Universidad Complutense de Madrid, Madrid, Spain
| | - María Luz Morales
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, Madrid, Spain
| | - Sophie Allain-Maillet
- Université de Nantes, Institut National de la Santé et de la Recherche Médicale (Inserm), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Nantes, France
| | - Nicolas Mennesson
- Université de Nantes, Institut National de la Santé et de la Recherche Médicale (Inserm), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Nantes, France
| | - Ricardo Sanchez
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, Madrid, Spain
| | - Rafael Alonso
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, Madrid, Spain
| | - Alejandra Leivas
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, Madrid, Spain
| | | | - Edith Bigot-Corbel
- Université de Nantes, Institut National de la Santé et de la Recherche Médicale (Inserm), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Nantes, France
- Laboratoire de Biochimie, Centre Hospitalier Universitaire (CHU) de Nantes, Nantes, France
| | - Sylvie Hermouet
- Université de Nantes, Institut National de la Santé et de la Recherche Médicale (Inserm), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Nantes, France
- Laboratoire d’Hématologie, Centre Hospitalier Universitaire (CHU) de Nantes, Nantes, France
| | - Joaquín Martínez-López
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, Madrid, Spain
- Department of Medicine, Medicine School, Universidad Complutense de Madrid, Madrid, Spain
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23
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Bende RJ, Janssen J, van Noesel CJM. Higher-order of chronic lymphocytic leukaemia (CLL) classification: shared antigenic specificities of stereotyped B-cell receptor subsets as defined by the European Research Initiative on CLL consortium. Br J Haematol 2021; 196:e60-e63. [PMID: 34796956 DOI: 10.1111/bjh.17964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 11/02/2021] [Accepted: 11/06/2021] [Indexed: 12/01/2022]
Affiliation(s)
- Richard J Bende
- Department of Pathology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.,Lymphoma and Myeloma Center Amsterdam - LYMMCARE, Amsterdam, The Netherlands
| | - Jerry Janssen
- Department of Pathology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.,Lymphoma and Myeloma Center Amsterdam - LYMMCARE, Amsterdam, The Netherlands
| | - Carel J M van Noesel
- Department of Pathology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.,Lymphoma and Myeloma Center Amsterdam - LYMMCARE, Amsterdam, The Netherlands
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24
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The Role of B-Cells and Antibodies against Candida Vaccine Antigens in Invasive Candidiasis. Vaccines (Basel) 2021; 9:vaccines9101159. [PMID: 34696267 PMCID: PMC8540628 DOI: 10.3390/vaccines9101159] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 10/04/2021] [Accepted: 10/07/2021] [Indexed: 01/08/2023] Open
Abstract
Systemic candidiasis is an invasive fungal infection caused by members of the genus Candida. The recent emergence of antifungal drug resistance and increased incidences of infections caused by non-albicans Candida species merit the need for developing immune therapies against Candida infections. Although the role of cellular immune responses in anti-Candida immunity is well established, less is known about the role of humoral immunity against systemic candidiasis. This review summarizes currently available information on humoral immune responses induced by several promising Candida vaccine candidates, which have been identified in the past few decades. The protective antibody and B-cell responses generated by polysaccharide antigens such as mannan, β-glucan, and laminarin, as well as protein antigens like agglutinin-like sequence gene (Als3), secreted aspartyl proteinase (Sap2), heat shock protein (Hsp90), hyphally-regulated protein (Hyr1), hyphal wall protein (Hwp1), enolase (Eno), phospholipase (PLB), pyruvate kinase (Pk), fructose bisphosphate aldolase (Fba1), superoxide dismutase gene (Sod5) and malate dehydrogenase (Mdh1), are outlined. As per studies reviewed, antibodies induced in response to leading Candida vaccine candidates contribute to protection against systemic candidiasis by utilizing a variety of mechanisms such as opsonization, complement fixation, neutralization, biofilm inhibition, direct candidacidal activity, etc. The contributions of B-cells in controlling fungal infections are also discussed. Promising results using anti-Candida monoclonal antibodies for passive antibody therapy reinforces the need for developing antibody-based therapeutics including anti-idiotypic antibodies, single-chain variable fragments, peptide mimotopes, and antibody-derived peptides. Future research involving combinatorial immunotherapies using humanized monoclonal antibodies along with antifungal drugs/cytokines may prove beneficial for treating invasive fungal infections.
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25
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A Major Subset of Mutated CLL Expresses Affinity-selected and Functionally Proficient Rheumatoid Factors. Hemasphere 2021; 5:e550. [PMID: 33778415 PMCID: PMC7990012 DOI: 10.1097/hs9.0000000000000550] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 02/15/2021] [Indexed: 11/25/2022] Open
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26
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Abstract
Patients with chronic lymphocytic leukemia can be divided into three categories: those who are minimally affected by the problem, often never requiring therapy; those that initially follow an indolent course but subsequently progress and require therapy; and those that from the point of diagnosis exhibit an aggressive disease necessitating treatment. Likewise, such patients pass through three phases: development of the disease, diagnosis, and need for therapy. Finally, the leukemic clones of all patients appear to require continuous input from the exterior, most often through membrane receptors, to allow them to survive and grow. This review is presented according to the temporal course that the disease follows, focusing on those external influences from the tissue microenvironment (TME) that support the time lines as well as those internal influences that are inherited or develop as genetic and epigenetic changes occurring over the time line. Regarding the former, special emphasis is placed on the input provided via the B-cell receptor for antigen and the C-X-C-motif chemokine receptor-4 and the therapeutic agents that block these inputs. Regarding the latter, prominence is laid upon inherited susceptibility genes and the genetic and epigenetic abnormalities that lead to the developmental and progression of the disease.
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MESH Headings
- Disease Progression
- Humans
- Immunotherapy
- Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis
- Leukemia, Lymphocytic, Chronic, B-Cell/etiology
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/therapy
- Mutation
- PAX5 Transcription Factor/metabolism
- Receptors, Antigen, B-Cell
- Signal Transduction
- Tumor Microenvironment
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Affiliation(s)
- Nicholas Chiorazzi
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York 11030, USA
| | - Shih-Shih Chen
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York 11030, USA
| | - Kanti R Rai
- The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York 11549, USA
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27
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Kikushige Y. Pathogenesis of chronic lymphocytic leukemia and the development of novel therapeutic strategies. J Clin Exp Hematop 2020; 60:146-158. [PMID: 33148933 PMCID: PMC7810248 DOI: 10.3960/jslrt.20036] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 10/05/2020] [Accepted: 10/06/2020] [Indexed: 12/15/2022] Open
Abstract
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries and is characterized by the clonal expansion of mature CD5+ B cells. There have been substantial advances in the field of CLL research in the last decade, including the identification of recurrent mutations, and clarification of clonal architectures, signaling molecules, and the multistep leukemogenic process, providing a comprehensive understanding of CLL pathogenesis. Furthermore, the development of therapeutic approaches, especially that of molecular target therapies against CLL, has markedly improved the standard of care for CLL. This review focuses on the recent insights made in CLL leukemogenesis and the development of novel therapeutic strategies.
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MESH Headings
- Adult
- Carcinogenesis/genetics
- Carcinogenesis/metabolism
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Leukemia, Lymphocytic, Chronic, B-Cell/therapy
- Molecular Targeted Therapy
- Mutation
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28
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Thurner L, Hartmann S, Neumann F, Hoth M, Stilgenbauer S, Küppers R, Preuss KD, Bewarder M. Role of Specific B-Cell Receptor Antigens in Lymphomagenesis. Front Oncol 2020; 10:604685. [PMID: 33363034 PMCID: PMC7756126 DOI: 10.3389/fonc.2020.604685] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 11/02/2020] [Indexed: 12/22/2022] Open
Abstract
The B-cell receptor (BCR) signaling pathway is a crucial pathway of B cells, both for their survival and for antigen-mediated activation, proliferation and differentiation. Its activation is also critical for the genesis of many lymphoma types. BCR-mediated lymphoma proliferation may be caused by activating BCR-pathway mutations and/or by active or tonic stimulation of the BCR. BCRs of lymphomas have frequently been described as polyreactive. In this review, the role of specific target antigens of the BCRs of lymphomas is highlighted. These antigens have been found to be restricted to specific lymphoma entities. The antigens can be of infectious origin, such as H. pylori in gastric MALT lymphoma or RpoC of M. catarrhalis in nodular lymphocyte predominant Hodgkin lymphoma, or they are autoantigens. Examples of such autoantigens are the BCR itself in chronic lymphocytic leukemia, LRPAP1 in mantle cell lymphoma, hyper-N-glycosylated SAMD14/neurabin-I in primary central nervous system lymphoma, hypo-phosphorylated ARS2 in diffuse large B-cell lymphoma, and hyper-phosphorylated SLP2, sumoylated HSP90 or saposin C in plasma cell dyscrasia. Notably, atypical posttranslational modifications are often responsible for the immunogenicity of many autoantigens. Possible therapeutic approaches evolving from these specific antigens are discussed.
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Affiliation(s)
- Lorenz Thurner
- Department of Internal Medicine I, José Carreras Center for Immuno- and Gene Therapy, Saarland University Medical School, Homburg, Germany
| | - Sylvia Hartmann
- Dr. Senckenberg Institute of Pathology, Goethe University, Frankfurt a. Main, Germany
| | - Frank Neumann
- Department of Internal Medicine I, José Carreras Center for Immuno- and Gene Therapy, Saarland University Medical School, Homburg, Germany
| | - Markus Hoth
- Department of Biophysics, Center for Integrative Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, Germany
| | - Stephan Stilgenbauer
- Department of Internal Medicine I, José Carreras Center for Immuno- and Gene Therapy, Saarland University Medical School, Homburg, Germany
| | - Ralf Küppers
- Medical School, Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany.,Deutsches Konsortium für translationale Krebsforschung (DKTK), Partner Site Essen, Essen, Germany
| | - Klaus-Dieter Preuss
- Department of Internal Medicine I, José Carreras Center for Immuno- and Gene Therapy, Saarland University Medical School, Homburg, Germany
| | - Moritz Bewarder
- Department of Internal Medicine I, José Carreras Center for Immuno- and Gene Therapy, Saarland University Medical School, Homburg, Germany
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29
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Haselager MV, Kater AP, Eldering E. Proliferative Signals in Chronic Lymphocytic Leukemia; What Are We Missing? Front Oncol 2020; 10:592205. [PMID: 33134182 PMCID: PMC7578574 DOI: 10.3389/fonc.2020.592205] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 09/18/2020] [Indexed: 12/23/2022] Open
Abstract
Chronic lymphocytic leukemia (CLL) cells cycle between lymphoid tissue sites where they actively proliferate, and the peripheral blood (PB) where they become quiescent. Strong evidence exists for a crucial role of B cell receptor (BCR) triggering, either by (self-)antigen or by receptor auto-engagement in the lymph node (LN) to drive CLL proliferation and provide adhesion. The clinical success of Bruton's tyrosine kinase (BTK) inhibitors is widely accepted to be based on blockade of the BCR signal. Additional signals in the LN that support CLL survival derive from surrounding cells, such as CD40L-presenting T helper cells, myeloid and stromal cells. It is not quite clear if and to what extent these non-BCR signals contribute to proliferation in situ. In vitro BCR triggering, in contrast, leads to low-level activation and does not result in cell division. Various combinations of non-BCR signals delivered via co-stimulatory receptors, Toll-like receptors (TLRs), and/or soluble cytokines are applied, leading to comparatively modest and short-lived CLL proliferation in vitro. Thus, an unresolved gap exists between the condition in the patient as we now understand it and applicable knowledge that can be harnessed in the laboratory for future therapeutic applications. Even in this era of targeted drugs, CLL remains largely incurable with frequent relapses and emergence of resistance. Therefore, we require better insight into all aspects of CLL growth and potential rewiring of signaling pathways. We aim here to provide an overview of in vivo versus in vitro signals involved in CLL proliferation, point out areas of missing knowledge and suggest future directions for research.
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Affiliation(s)
- Marco V. Haselager
- Department of Experimental Immunology, Academic University Medical Center, location Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
- Lymphoma and Myeloma Center Amsterdam, LYMMCARE, Amsterdam, Netherlands
- Cancer Center Amsterdam, LYMMCARE, Amsterdam, Netherlands
- Amsterdam Infection & Immunity Institute, Amsterdam, Netherlands
| | - Arnon P. Kater
- Cancer Center Amsterdam, LYMMCARE, Amsterdam, Netherlands
- Amsterdam Infection & Immunity Institute, Amsterdam, Netherlands
- Department of Hematology, Academic University Medical Center, location Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Eric Eldering
- Department of Experimental Immunology, Academic University Medical Center, location Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
- Lymphoma and Myeloma Center Amsterdam, LYMMCARE, Amsterdam, Netherlands
- Cancer Center Amsterdam, LYMMCARE, Amsterdam, Netherlands
- Amsterdam Infection & Immunity Institute, Amsterdam, Netherlands
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30
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MESH Headings
- Antineoplastic Agents/adverse effects
- Antineoplastic Agents/history
- Antineoplastic Agents/therapeutic use
- Antineoplastic Agents, Immunological/therapeutic use
- Drug Resistance, Neoplasm
- Female
- History, 20th Century
- History, 21st Century
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Male
- Mutation
- Prognosis
- Receptors, Antigen, B-Cell/genetics
- Receptors, Antigen, B-Cell/metabolism
- Signal Transduction
- Survival Rate
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Affiliation(s)
- Jan A Burger
- From the Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston
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31
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Netea MG, Domínguez-Andrés J, Barreiro LB, Chavakis T, Divangahi M, Fuchs E, Joosten LAB, van der Meer JWM, Mhlanga MM, Mulder WJM, Riksen NP, Schlitzer A, Schultze JL, Stabell Benn C, Sun JC, Xavier RJ, Latz E. Defining trained immunity and its role in health and disease. Nat Rev Immunol 2020; 20:375-388. [PMID: 32132681 PMCID: PMC7186935 DOI: 10.1038/s41577-020-0285-6] [Citation(s) in RCA: 1467] [Impact Index Per Article: 293.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/24/2020] [Indexed: 12/14/2022]
Abstract
Immune memory is a defining feature of the acquired immune system, but activation of the innate immune system can also result in enhanced responsiveness to subsequent triggers. This process has been termed 'trained immunity', a de facto innate immune memory. Research in the past decade has pointed to the broad benefits of trained immunity for host defence but has also suggested potentially detrimental outcomes in immune-mediated and chronic inflammatory diseases. Here we define 'trained immunity' as a biological process and discuss the innate stimuli and the epigenetic and metabolic reprogramming events that shape the induction of trained immunity.
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Affiliation(s)
- Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands.
- Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.
- Department of Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
| | - Jorge Domínguez-Andrés
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands
- Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Luis B Barreiro
- Department of Genetics, CHU Sainte-Justine Research Centre, Montreal, QC, Canada
- Department of Pediatrics, University of Montreal, Montreal, QC, Canada
- Genetics Section, Department of Medicine, The University of Chicago, Chicago, IL, USA
| | - Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden, Germany
- Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Maziar Divangahi
- Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
- McGill International TB Centre, McGill University Health Centre, Montreal, QC, Canada
| | - Elaine Fuchs
- Howard Hughes Medical Institute, Robin Chemers Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY, USA
| | - Leo A B Joosten
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands
- Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Jos W M van der Meer
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands
- Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Musa M Mhlanga
- Division of Chemical and Systems Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
- Gene Expression and Biophysics Unit, Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisbon, Portugal
| | - Willem J M Mulder
- Translational and Molecular Imaging Institute, Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, Netherlands
| | - Niels P Riksen
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands
- Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Andreas Schlitzer
- Myeloid Cell Biology, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany
| | - Joachim L Schultze
- Department of Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany
| | - Christine Stabell Benn
- Bandim Health Project, OPEN, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Joseph C Sun
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY, USA
| | - Ramnik J Xavier
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Eicke Latz
- Institute of Innate Immunity, University Hospital, University of Bonn, Bonn, Germany.
- Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA.
- German Center for Neurodegenerative Diseases, Bonn, Germany.
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32
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Mechanisms of B Cell Receptor Activation and Responses to B Cell Receptor Inhibitors in B Cell Malignancies. Cancers (Basel) 2020; 12:cancers12061396. [PMID: 32481736 PMCID: PMC7352865 DOI: 10.3390/cancers12061396] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 05/22/2020] [Accepted: 05/25/2020] [Indexed: 12/27/2022] Open
Abstract
The B cell receptor (BCR) pathway has been identified as a potential therapeutic target in a number of common B cell malignancies, including chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone B cell lymphoma, and Waldenstrom's macroglobulinemia. This finding has resulted in the development of numerous drugs that target this pathway, including various inhibitors of the kinases BTK, PI3K, and SYK. Several of these drugs have been approved in recent years for clinical use, resulting in a profound change in the way these diseases are currently being treated. However, the response rates and durability of responses vary largely across the different disease entities, suggesting a different proportion of patients with an activated BCR pathway and different mechanisms of BCR pathway activation. Indeed, several antigen-dependent and antigen-independent mechanisms have recently been described and shown to result in the activation of distinct downstream signaling pathways. The purpose of this review is to provide an overview of the mechanisms responsible for the activation of the BCR pathway in different B cell malignancies and to correlate these mechanisms with clinical responses to treatment with BCR inhibitors.
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Celebrating 20 Years of IGHV Mutation Analysis in CLL. Hemasphere 2020; 4:e334. [PMID: 32382709 PMCID: PMC7000474 DOI: 10.1097/hs9.0000000000000334] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 11/28/2019] [Accepted: 12/13/2019] [Indexed: 12/22/2022] Open
Abstract
The division of CLL into 2 broad subsets with highly significant differences in clinical behavior was reported in 2 landmark papers in Blood in 1999.1,2 The simple analysis of the mutational status of the IGV regions provided both a prognostic indicator and an insight into the cellular origins. Derivation from B cells with very low or no IGV mutations generally leads to a more aggressive disease course than derivation from B cells with higher levels. This finding focused attention on surface Ig (sIg), the major B-cell receptor, and revealed dynamic antigen engagement in vivo as a tumor driver. It has also led to new drugs aimed at components of the intracellular activation cascades. After 20 years, the 2 senior authors of those papers have looked at the history of the observations and at the increasing understanding of the role of sIg in CLL that have emanated from them. As in the past, studies of CLL have provided a link between biology and the clinic, enabling more precise targeting which attacks critical pathways but minimizes side effects.
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Kikushige Y. Pathophysiology of chronic lymphocytic leukemia and human B1 cell development. Int J Hematol 2019; 111:634-641. [PMID: 31797231 DOI: 10.1007/s12185-019-02788-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 11/28/2019] [Accepted: 11/28/2019] [Indexed: 12/22/2022]
Abstract
Chronic lymphocytic leukemia (CLL), the most frequent type of leukemia in adults, is a lymphoproliferative disease characterized by the clonal expansion of mature CD5+ B cells in peripheral blood, bone marrow, and secondary lymphoid tissues. Over the past decade, substantial advances have been made in understanding the pathogenesis of CLL, including the identification of recurrent mutations, and clarification of clonal architectures, transcriptome analyses, and the multistep leukemogenic process. The biology of CLL is now better understood. The present review focuses on recent insights into CLL leukemogenesis, emphasizing the role of genetic lesions, and the multistep process initiating from very immature hematopoietic stem cells. Finally, we also review progress in the study of human B1 B cells, the putative normal counterparts of CLL cells.
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Affiliation(s)
- Yoshikane Kikushige
- Department of Medicine and Biosystemic Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.
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Puła B, Gołos A, Górniak P, Jamroziak K. Overcoming Ibrutinib Resistance in Chronic Lymphocytic Leukemia. Cancers (Basel) 2019; 11:E1834. [PMID: 31766355 PMCID: PMC6966427 DOI: 10.3390/cancers11121834] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Revised: 11/15/2019] [Accepted: 11/19/2019] [Indexed: 12/11/2022] Open
Abstract
Ibrutinib is the first Bruton's tyrosine kinase (BTK) inhibitor, which showed significant clinical activity in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) patients regardless of cytogenetic risk factors. Recent results of phase III clinical trials in treatment-naïve CLL patients shift the importance of the agent to frontline therapy. Nevertheless, beside its clinical efficacy, ibrutinib possesses some off-target activity resulting in ibrutinib-characteristic adverse events including bleeding diathesis and arrhythmias. Furthermore, acquired and primary resistance to the drug have been described. As the use of ibrutinib in clinical practice increases, the problem of resistance is becoming apparent, and new methods of overcoming this clinical problem arise. In this review, we summarize the mechanisms of BTK inhibitors' resistance and discuss the post-ibrutinib treatment options.
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Affiliation(s)
- Bartosz Puła
- Department of Hematology, Institute of Hematology and Transfusion Medicine, 02-776 Warsaw, Poland;
| | - Aleksandra Gołos
- Institute of Hematology and Transfusion Medicine, 02-776 Warsaw, Poland;
| | - Patryk Górniak
- Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, 02-776 Warsaw, Poland;
| | - Krzysztof Jamroziak
- Department of Hematology, Institute of Hematology and Transfusion Medicine, 02-776 Warsaw, Poland;
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36
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Molecular modelling of epitopes recognized by neoplastic B lymphocytes in Chronic Lymphocytic Leukemia. Eur J Med Chem 2019; 185:111838. [PMID: 31718942 DOI: 10.1016/j.ejmech.2019.111838] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 10/29/2019] [Accepted: 10/30/2019] [Indexed: 12/22/2022]
Abstract
Identification of epitopes recognized by tumour B cells could provide insights into the molecular mechanisms of B cell tumorigenesis through aberrant B cell receptor (BCR) signalling. Here, we analysed the structure of eleven peptides binders of BCRs expressed in Chronic Lymphocytic Leukemia (CLL) patients in order to identify the chemical features required for cross-reactive binding to different CLL clonotypes. Four cross-reactive (CR) and seven no-cross-reactive (NCR) peptides were analysed by means of GRID molecular interaction fields, ligand-based pharmacophore and 3D-QSAR approaches. Based on pharmacophore model, two peptides were generated by specific amino acids substitutions of the parental NCR peptides; these new peptides resumed the common chemical features of CR peptides and bound the CLL BCR clonotypes recognized by CR peptides and parental NCR peptides. Thus, our computational approach guided the pharmacophore modelling of CR peptides. In perspective, peptide binders of CLL BCR clonotypes could represent a powerful tool for computational modelling of epitopes recognized by tumour B cells clones.
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Stranska K, Plevova K, Skuhrova Francova H, Skabrahova H, von Jagwitz-Biegnitz M, Radova L, Panovska A, Hrobkova S, Brychtova Y, Urbanova R, Smolej L, Simkovic M, Zuchnicka J, Mohammadova L, Spacek M, Mayer J, Pospisilova S, Doubek M. Profiling of biological and environmental risk factors in immunogenetic subgroups of chronic lymphocytic leukemia - Czech national study. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2019; 164:425-434. [PMID: 31558845 DOI: 10.5507/bp.2019.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 09/04/2019] [Indexed: 11/23/2022] Open
Abstract
AIMS This is a nation-wide survey of chronic lymphocytic leukemia (CLL) patients at six large hematology centers in the Czech Republic. The aim was to identify specific populations, social, and health characteristics of CLL subgroups divided according to the immunogenetic features of their B cell receptors (BCRs) and clonality. PATIENTS AND METHODS Questionnaires directed to specific health, social, and environmental conditions were collected in a cohort of 573 CLL patients. For these patients, immunoglobulin heavy chain gene rearrangements were also analyzed in order to gain information about their clonality, IGHV mutational status, and the presence of stereotyped BCRs. Data extracted from the questionnaires were analyzed statistically in the context of immunogenetic features of the cohort. RESULTS There were no statistically significant differences in the data collected in the survey between patients with mutated and patients with unmutated IGHV. However, patients with oligoclonal CLL reported health conditions such as hypercholesterolemia, hypertension, herpes simplex, tumors, and also, separately, CLL in 1st degree relatives, more often than their monoclonal counterparts. In patients with stereotyped BCRs, we found more frequent alcohol consumption and gastric infections in subset #1 cases and frequent cholecystectomies and familial CLL in subset #2 cases. CONCLUSION To the best of our knowledge, this study is the first to investigate CLL immunogenetic features and clonality in the context of epidemiological data. We reported statistically significant associations suggesting the influence of certain health and social conditions on a number of clonal populations expanding in CLL and also on characteristic BCR features, especially stereotypy.
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Affiliation(s)
- Kamila Stranska
- Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.,Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Karla Plevova
- Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.,Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Hana Skuhrova Francova
- Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Hana Skabrahova
- Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Magdalena von Jagwitz-Biegnitz
- Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Lenka Radova
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Anna Panovska
- Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Stanislava Hrobkova
- Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Yvona Brychtova
- Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Renata Urbanova
- Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Czech Republic
| | | | | | - Jana Zuchnicka
- Department of Hematooncology, University Hospital Ostrava, Czech Republic
| | - Lekaa Mohammadova
- Department of Hematology and Oncology, University Hospital Pilsen, Czech Republic
| | | | - Jiri Mayer
- Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Sarka Pospisilova
- Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.,Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Michael Doubek
- Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.,Central European Institute of Technology, Masaryk University, Brno, Czech Republic
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Ziegler CGK, Kim J, Piersanti K, Oyler-Yaniv A, Argyropoulos KV, van den Brink MRM, Palomba ML, Altan-Bonnet N, Altan-Bonnet G. Constitutive Activation of the B Cell Receptor Underlies Dysfunctional Signaling in Chronic Lymphocytic Leukemia. Cell Rep 2019; 28:923-937.e3. [PMID: 31340154 PMCID: PMC8018719 DOI: 10.1016/j.celrep.2019.06.069] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 05/18/2019] [Accepted: 06/19/2019] [Indexed: 12/31/2022] Open
Abstract
In cancer biology, the functional interpretation of genomic alterations is critical to achieve the promise of genomic profiling in the clinic. For chronic lymphocytic leukemia (CLL), a heterogeneous disease of B-lymphocytes maturing under constitutive B cell receptor (BCR) stimulation, the functional role of diverse clonal mutations remains largely unknown. Here, we demonstrate that alterations in BCR signaling dynamics underlie the progression of B cells toward malignancy. We reveal emergent dynamic features—bimodality, hypersensitivity, and hysteresis—in the BCR signaling pathway of primary CLL B cells. These signaling abnormalities in CLL quantitatively derive from BCR clustering and constitutive signaling with positive feedback reinforcement, as demonstrated through single-cell analysis of phospho-responses, computational modeling, and super-resolution imaging. Such dysregulated signaling segregates CLL patients by disease severity and clinical presentation. These findings provide a quantitative framework and methodology to assess complex and heterogeneous leukemia pathology and to inform therapeutic strategies in parallel with genomic profiling. Using phospho-flow cytometry and computational modeling, Ziegler et al. find that B cell receptor clustering and positive feedback through SYK and LYN drive signaling hypersensitivity, bistability, and hysteresis in chronic lymphocytic leukemic B cells. Super-resolution microscopy confirms membrane auto-aggregation in leukemic B cells, and variability in signaling dysfunction predicts disease severity.
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Affiliation(s)
- Carly G K Ziegler
- ImmunoDynamics Group, Programs in Computational Biology and Immunology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Cancer Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
| | - Joel Kim
- ImmunoDynamics Group, Programs in Computational Biology and Immunology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Cancer Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Kelly Piersanti
- Center for Cancer Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Alon Oyler-Yaniv
- ImmunoDynamics Group, Programs in Computational Biology and Immunology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Physics Department, Ben Gurion University, Beer-Sheva, Israel
| | - Kimon V Argyropoulos
- Center for Cancer Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Marcel R M van den Brink
- Center for Cancer Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - M Lia Palomba
- Center for Cancer Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | | | - Grégoire Altan-Bonnet
- ImmunoDynamics Group, Programs in Computational Biology and Immunology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Cancer Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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Meijers RWJ, Muggen AF, Leon LG, de Bie M, van Dongen JJM, Hendriks RW, Langerak AW. Responsiveness of chronic lymphocytic leukemia cells to B-cell receptor stimulation is associated with low expression of regulatory molecules of the nuclear factor-κB pathway. Haematologica 2019; 105:182-192. [PMID: 31097630 PMCID: PMC6939541 DOI: 10.3324/haematol.2018.215566] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Accepted: 05/15/2019] [Indexed: 11/09/2022] Open
Abstract
Chronic lymphocytic leukemia (CLL) is a disease with heterogeneous clinical and biological characteristics. Differences in Ca2+ levels among cases, both basal and upon B-cell receptor (BCR) stimulation, may reflect heterogeneity in the pathogenesis due to cell-intrinsic factors. Our aim was to elucidate cell-intrinsic differences between BCR-responsive and -unresponsive cases. We therefore determined BCR responsiveness ex vivo based on Ca2+ influx upon α-IgM stimulation of purified CLL cell fractions from 52 patients. Phosphorylation levels of various BCR signaling molecules, and expression of activation markers were assessed by flow cytometry. Transcription profiling of responsive (n=6) and unresponsive cases (n=6) was performed by RNA sequencing. Real-time quantitative polymerase chain reaction analysis was used to validate transcript level differences in a larger cohort. In 24 cases an α-IgM response was visible by Ca2+ influx which was accompanied by higher phosphorylation of PLCγ2 and Akt after α-IgM stimulation in combination with higher surface expression of IgM, IgD, CD19, CD38 and CD43 compared to the unresponsive cases (n=28). Based on RNA sequencing analysis several components of the canonical nuclear factor (NF)-κB pathway, especially those related to NF-κB inhibition, were expressed more highly in unresponsive cases. Moreover, upon α-IgM stimulation, the expression of these NF-κB pathway genes (especially genes coding for NF-κB pathway inhibitors but also NF-κB subunit REL) was upregulated in BCR-responsive cases while the level did not change, compared to basal level, in the unresponsive cases. These findings suggest that cells from CLL cases with enhanced NF-κB signaling have a lesser capacity to respond to BCR stimulation.
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Affiliation(s)
- Ruud W J Meijers
- Laboratory Medical Immunology, Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam
| | - Alice F Muggen
- Laboratory Medical Immunology, Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam
| | - Leticia G Leon
- Laboratory Medical Immunology, Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam
| | - Maaike de Bie
- Laboratory Medical Immunology, Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam
| | - Jacques J M van Dongen
- Laboratory Medical Immunology, Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam.,Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden
| | - Rudi W Hendriks
- Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands
| | - Anton W Langerak
- Laboratory Medical Immunology, Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam
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Gupta R, Li W, Yan XJ, Barrientos J, Kolitz JE, Allen SL, Rai K, Chiorazzi N, Mongini PKA. Mechanism for IL-15-Driven B Cell Chronic Lymphocytic Leukemia Cycling: Roles for AKT and STAT5 in Modulating Cyclin D2 and DNA Damage Response Proteins. THE JOURNAL OF IMMUNOLOGY 2019; 202:2924-2944. [PMID: 30988120 DOI: 10.4049/jimmunol.1801142] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Accepted: 03/13/2019] [Indexed: 12/25/2022]
Abstract
Clonal expansion of B cell chronic lymphocytic leukemia (B-CLL) occurs within lymphoid tissue pseudofollicles. IL-15, a stromal cell-associated cytokine found within spleens and lymph nodes of B-CLL patients, significantly boosts in vitro cycling of blood-derived B-CLL cells following CpG DNA priming. Both IL-15 and CpG DNA are elevated in microbe-draining lymphatic tissues, and unraveling the basis for IL-15-driven B-CLL growth could illuminate new therapeutic targets. Using CpG DNA-primed human B-CLL clones and approaches involving both immunofluorescent staining and pharmacologic inhibitors, we show that both PI3K/AKT and JAK/STAT5 pathways are activated and functionally important for IL-15→CD122/ɣc signaling in ODN-primed cells expressing activated pSTAT3. Furthermore, STAT5 activity must be sustained for continued cycling of CFSE-labeled B-CLL cells. Quantitative RT-PCR experiments with inhibitors of PI3K and STAT5 show that both contribute to IL-15-driven upregulation of mRNA for cyclin D2 and suppression of mRNA for DNA damage response mediators ATM, 53BP1, and MDC1. Furthermore, protein levels of these DNA damage response molecules are reduced by IL-15, as indicated by Western blotting and immunofluorescent staining. Bioinformatics analysis of ENCODE chromatin immunoprecipitation sequencing data from cell lines provides insight into possible mechanisms for STAT5-mediated repression. Finally, pharmacologic inhibitors of JAKs and STAT5 significantly curtailed B-CLL cycling when added either early or late in a growth response. We discuss how the IL-15-induced changes in gene expression lead to rapid cycling and possibly enhanced mutagenesis. STAT5 inhibitors might be an effective modality for blocking B-CLL growth in patients.
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Affiliation(s)
- Rashmi Gupta
- The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030
| | - Wentian Li
- The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030
| | - Xiao J Yan
- The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030
| | | | - Jonathan E Kolitz
- The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030.,Department of Medicine, Northwell Health, Manhasset, NY 11030.,Department of Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549; and
| | - Steven L Allen
- The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030.,Department of Medicine, Northwell Health, Manhasset, NY 11030.,Department of Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549; and
| | - Kanti Rai
- The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030.,Department of Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549; and.,Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549
| | - Nicholas Chiorazzi
- The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030.,Department of Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549; and.,Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549
| | - Patricia K A Mongini
- The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030; .,Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549
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Casola S, Perucho L, Tripodo C, Sindaco P, Ponzoni M, Facchetti F. The B‐cell receptor in control of tumor B‐cell fitness: Biology and clinical relevance. Immunol Rev 2019; 288:198-213. [DOI: 10.1111/imr.12738] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 01/07/2019] [Accepted: 01/10/2019] [Indexed: 12/15/2022]
Affiliation(s)
- Stefano Casola
- The FIRC Institute of Molecular Oncology (IFOM) Milan Italy
| | - Laura Perucho
- The FIRC Institute of Molecular Oncology (IFOM) Milan Italy
| | - Claudio Tripodo
- Tumor Immunology UnitDepartment of Health SciencesUniversity of Palermo Palermo Italy
- Tumor and Microenvironment Histopathology UnitThe FIRC Institute of Molecular Oncology (IFOM) Milan Italy
| | - Paola Sindaco
- Department of Emergency and Organ Transplantation (D.E.T.O.)Hematology SectionUniversity of Bari Bari Italy
| | - Maurilio Ponzoni
- Pathology and Lymphoid Malignancies UnitsAteneo Vita‐Salute San Raffaele Scientific Institute Milan Italy
| | - Fabio Facchetti
- Department of Molecular and Translational MedicineSection of PathologyUniversity of Brescia Brescia Italy
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42
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Presence of serum antinuclear antibodies correlating unfavorable overall survival in patients with chronic lymphocytic leukemia. Chin Med J (Engl) 2019; 132:525-533. [PMID: 30741830 PMCID: PMC6415995 DOI: 10.1097/cm9.0000000000000114] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Background: Serum antinuclear antibodies (ANAs) are positive in some patients with chronic lymphocytic leukemia (CLL), but the prognostic value of ANAs remains unknown. The aim of this study was to evaluate the role of ANAs as a prognostic factor in CLL. Methods: This study retrospectively analyzed clinical data from 216 newly diagnosed CLL subjects with ANAs test from 2007 to 2017. Multivariate Cox regression analyses were used to screen the independent prognostic factors related to time to first treatment (TTFT), progression free survival (PFS) and overall survival (OS). Receiver operator characteristic curves and area under the curve (AUC) were utilized to assess the predictive accuracy of ANAs together with other independent factors for OS. Results: The incidence of ANAs abnormality at diagnosis was 13.9%. ANAs positivity and TP53 disruption were independent prognostic indicators for OS. The AUC of positive ANAs together with TP53 disruption was 0.766 (95% confidence interval [CI]: 0.697–0.826), which was significantly larger than that of either TP53 disruption (AUC: 0.706, 95% CI: 0.634–0.772, P = 0.034) or positive ANAs (AUC: 0.595, 95% CI: 0.520–0.668, P < 0.001) in OS prediction. Besides, serum positive ANAs as one additional parameter to CLL-international prognostic index (IPI) obtained superior AUCs in predicting CLL OS than CLL-IPI alone. Conclusion: This study identified ANAs as an independent prognostic factor for CLL, and further investigations are needed to validate this finding.
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43
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Schleiss C, Ilias W, Tahar O, Güler Y, Miguet L, Mayeur-Rousse C, Mauvieux L, Fornecker LM, Toussaint E, Herbrecht R, Bertrand F, Maumy-Bertrand M, Martin T, Fournel S, Georgel P, Bahram S, Vallat L. BCR-associated factors driving chronic lymphocytic leukemia cells proliferation ex vivo. Sci Rep 2019; 9:701. [PMID: 30679590 PMCID: PMC6345919 DOI: 10.1038/s41598-018-36853-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 11/21/2018] [Indexed: 01/18/2023] Open
Abstract
A chronic antigenic stimulation is believed to sustain the leukemogenic development of chronic lymphocytic leukemia (CLL) and most of lymphoproliferative malignancies developed from mature B cells. Reproducing a proliferative stimulation ex vivo is critical to decipher the mechanisms of leukemogenesis in these malignancies. However, functional studies of CLL cells remains limited since current ex vivo B cell receptor (BCR) stimulation protocols are not sufficient to induce the proliferation of these cells, pointing out the need of mandatory BCR co-factors in this process. Here, we investigated benefits of several BCR co-stimulatory molecules (IL-2, IL-4, IL-15, IL-21 and CD40 ligand) in multiple culture conditions. Our results demonstrated that BCR engagement (anti-IgM ligation) concomitant to CD40 ligand, IL-4 and IL-21 stimulation allowed CLL cells proliferation ex vivo. In addition, we established a proliferative advantage for ZAP70 positive CLL cells, associated to an increased phosphorylation of ZAP70/SYK and STAT6. Moreover, the use of a tri-dimensional matrix of methylcellulose and the addition of TLR9 agonists further increased this proliferative response. This ex vivo model of BCR stimulation with T-derived cytokines is a relevant and efficient model for functional studies of CLL as well as lymphoproliferative malignancies.
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Affiliation(s)
- Cédric Schleiss
- Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR-S1109, LabEx Transplantex, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.,Fédération Hospitalo-Universitaire (FHU) OMICARE, Université de Strasbourg, Strasbourg, France
| | - Wassila Ilias
- Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR-S1109, LabEx Transplantex, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.,Fédération Hospitalo-Universitaire (FHU) OMICARE, Université de Strasbourg, Strasbourg, France
| | - Ouria Tahar
- Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR-S1109, LabEx Transplantex, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.,Fédération Hospitalo-Universitaire (FHU) OMICARE, Université de Strasbourg, Strasbourg, France.,Laboratoire d'Immunologie, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Strasbourg, France
| | - Yonca Güler
- Université de Strasbourg, INSERM, IRFAC UMR-S1113, Strasbourg, France
| | - Laurent Miguet
- Université de Strasbourg, INSERM, IRFAC UMR-S1113, Strasbourg, France.,Laboratoire d'Hématologie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Caroline Mayeur-Rousse
- Université de Strasbourg, INSERM, IRFAC UMR-S1113, Strasbourg, France.,Laboratoire d'Hématologie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Laurent Mauvieux
- Université de Strasbourg, INSERM, IRFAC UMR-S1113, Strasbourg, France.,Laboratoire d'Hématologie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Luc-Matthieu Fornecker
- Université de Strasbourg, INSERM, IRFAC UMR-S1113, Strasbourg, France.,Service d'Hématologie Adulte, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Elise Toussaint
- Université de Strasbourg, INSERM, IRFAC UMR-S1113, Strasbourg, France.,Service d'Hématologie Adulte, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Raoul Herbrecht
- Université de Strasbourg, INSERM, IRFAC UMR-S1113, Strasbourg, France.,Service d'Hématologie Adulte, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Frédéric Bertrand
- Fédération Hospitalo-Universitaire (FHU) OMICARE, Université de Strasbourg, Strasbourg, France.,Institut de Recherche Mathématique Avancée IRMA, CNRS UMR 7501, Strasbourg, France
| | - Myriam Maumy-Bertrand
- Fédération Hospitalo-Universitaire (FHU) OMICARE, Université de Strasbourg, Strasbourg, France.,Institut de Recherche Mathématique Avancée IRMA, CNRS UMR 7501, Strasbourg, France
| | - Thierry Martin
- Fédération Hospitalo-Universitaire (FHU) OMICARE, Université de Strasbourg, Strasbourg, France.,CNRS UPR 9021 - Immunologie et Chimie Thérapeutiques, Institut de Biologie Moléculaire et cellulaire (IBMC), Strasbourg, France
| | - Sylvie Fournel
- CNRS UMR7199, Université de Strasbourg, Illkirch, France
| | - Philippe Georgel
- Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR-S1109, LabEx Transplantex, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.,Fédération Hospitalo-Universitaire (FHU) OMICARE, Université de Strasbourg, Strasbourg, France
| | - Seiamak Bahram
- Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR-S1109, LabEx Transplantex, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France. .,Fédération Hospitalo-Universitaire (FHU) OMICARE, Université de Strasbourg, Strasbourg, France. .,Laboratoire d'Immunologie, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Strasbourg, France.
| | - Laurent Vallat
- Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR-S1109, LabEx Transplantex, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France. .,Fédération Hospitalo-Universitaire (FHU) OMICARE, Université de Strasbourg, Strasbourg, France. .,Laboratoire d'Immunologie, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Strasbourg, France. .,Université de Strasbourg, INSERM, IRFAC UMR-S1113, and Laboratoire d'Hématologie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
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Scarfò L, Ghia P. Chronic Lymphocytic Leukemia: Who, How, and Where? HEMATOLOGIC MALIGNANCIES 2019:3-17. [DOI: 10.1007/978-3-030-11392-6_1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Ten Hacken E, Gounari M, Ghia P, Burger JA. The importance of B cell receptor isotypes and stereotypes in chronic lymphocytic leukemia. Leukemia 2018; 33:287-298. [PMID: 30555163 DOI: 10.1038/s41375-018-0303-x] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 08/29/2018] [Accepted: 10/08/2018] [Indexed: 12/14/2022]
Abstract
B cell receptor (BCR) signaling is a central pathway promoting the survival and proliferation of normal and malignant B cells. Chronic lymphocytic leukemia (CLL) arises from mature B cells, expressing functional BCRs, mainly of immunoglobulin M (IgM) and IgD isotypes. Importantly, 30% of CLL patients express quasi-identical BCRs, the so-called "stereotyped" receptors, indicating the existence of common antigenic determinants, which may drive disease initiation and favor its progression. Although the antigenic specificity of IgM and IgD receptors is identical, there are distinct isotype-specific responses after IgM and IgD triggering. Here, we discuss the most important steps of normal B cell development, and highlight the importance of BCR signaling for CLL pathogenesis, with a focus on differences between IgM and IgD isotype signaling. We also highlight the main characteristics of CLL patient subsets, based on BCR stereotypy, and describe subset-specific BCR function and antigen-binding characteristics. Finally, we outline the key biologic and clinical responses to kinase inhibitor therapy, targeting the BCR-associated Bruton's tyrosine kinase, phosphoinositide-3-kinase, and spleen tyrosine kinase in patients with CLL.
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Affiliation(s)
- Elisa Ten Hacken
- Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA
| | - Maria Gounari
- Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
| | - Paolo Ghia
- Strategic Research Program on CLL, IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milan, Italy
| | - Jan A Burger
- Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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46
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De novo gene mutations in normal human memory B cells. Leukemia 2018; 33:1219-1230. [PMID: 30353030 DOI: 10.1038/s41375-018-0289-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 08/20/2018] [Accepted: 08/31/2018] [Indexed: 12/12/2022]
Abstract
In the past years, the genomes of thousands of tumors have been elucidated. To date however, our knowledge on somatic gene alterations in normal cells is very limited. In this study, we demonstrate that tetanus-specific human memory B lymphocytes carry a substantial number of somatic mutations in the coding regions of the genome. Interestingly, we observed a statistically significant correlation between the number of exome mutations and those present in the immunoglobulin heavy variable regions. Our findings indicate that the majority of these genomic mutations arise in an antigen-dependent fashion, most likely during clonal expansion in germinal centers. The knowledge that normal B cells accumulate genomic alterations outside the immunoglobulin loci during development is relevant for our understanding of the process of lymphomagenesis.
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Burger JA, O'Brien S. Evolution of CLL treatment - from chemoimmunotherapy to targeted and individualized therapy. Nat Rev Clin Oncol 2018; 15:510-527. [PMID: 29777163 DOI: 10.1038/s41571-018-0037-8] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
During the past 5 years, a number of highly active novel agents, including kinase inhibitors targeting BTK or PI3Kδ, an antagonist of the antiapoptotic protein BCL-2, and new anti-CD20 monoclonal antibodies, have been added to the therapeutic armamentarium for patients with chronic lymphocytic leukaemia (CLL). In these exciting times, care is needed to optimally integrate these novel agents into the traditional treatment algorithm without overlooking or compromising the benefits of established treatments, especially chemoimmunotherapy. A more personalized approach to CLL therapy that takes into account individual risk factors, patient characteristics, and their treatment preferences is now possible. Herein, we discuss the biological basis for the novel therapeutic agents and outline not only the major advantages of these agents over traditional therapies but also their adverse effects and the rationale for continued use of older versus newer types of therapy for selected patients with CLL. We conclude by providing recommendations for an individualized therapy approach for different populations of patients with CLL.
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MESH Headings
- Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors
- Agammaglobulinaemia Tyrosine Kinase/immunology
- Antineoplastic Combined Chemotherapy Protocols
- Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors
- Class I Phosphatidylinositol 3-Kinases/immunology
- Humans
- Immunotherapy/trends
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/immunology
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Molecular Targeted Therapy
- Precision Medicine
- Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors
- Proto-Oncogene Proteins c-bcl-2/immunology
- Risk Factors
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Affiliation(s)
- Jan A Burger
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Susan O'Brien
- Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA, USA
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48
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Romero-Masters JC, Ohashi M, Djavadian R, Eichelberg MR, Hayes M, Bristol JA, Ma S, Ranheim EA, Gumperz J, Johannsen EC, Kenney SC. An EBNA3C-deleted Epstein-Barr virus (EBV) mutant causes B-cell lymphomas with delayed onset in a cord blood-humanized mouse model. PLoS Pathog 2018; 14:e1007221. [PMID: 30125329 PMCID: PMC6117096 DOI: 10.1371/journal.ppat.1007221] [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: 03/15/2018] [Revised: 08/30/2018] [Accepted: 07/16/2018] [Indexed: 12/15/2022] Open
Abstract
EBV causes human B-cell lymphomas and transforms B cells in vitro. EBNA3C, an EBV protein expressed in latently-infected cells, is required for EBV transformation of B cells in vitro. While EBNA3C undoubtedly plays a key role in allowing EBV to successfully infect B cells, many EBV+ lymphomas do not express this protein, suggesting that cellular mutations and/or signaling pathways may obviate the need for EBNA3C in vivo under certain conditions. EBNA3C collaborates with EBNA3A to repress expression of the CDKN2A-encoded tumor suppressors, p16 and p14, and EBNA3C-deleted EBV transforms B cells containing a p16 germline mutation in vitro. Here we have examined the phenotype of an EBNAC-deleted virus (Δ3C EBV) in a cord blood-humanized mouse model (CBH). We found that the Δ3C virus induced fewer lymphomas (occurring with a delayed onset) in comparison to the wild-type (WT) control virus, although a subset (10/26) of Δ3C-infected CBH mice eventually developed invasive diffuse large B cell lymphomas with type III latency. Both WT and Δ3C viruses induced B-cell lymphomas with restricted B-cell populations and heterogeneous T-cell infiltration. In comparison to WT-infected tumors, Δ3C-infected tumors had greatly increased p16 levels, and RNA-seq analysis revealed a decrease in E2F target gene expression. However, we found that Δ3C-infected tumors expressed c-Myc and cyclin E at similar levels compared to WT-infected tumors, allowing cells to at least partially bypass p16-mediated cell cycle inhibition. The anti-apoptotic proteins, BCL2 and IRF4, were expressed in Δ3C-infected tumors, likely helping cells avoid c-Myc-induced apoptosis. Unexpectedly, Δ3C-infected tumors had increased T-cell infiltration, increased expression of T-cell chemokines (CCL5, CCL20 and CCL22) and enhanced type I interferon response in comparison to WT tumors. Together, these results reveal that EBNA3C contributes to, but is not essential for, EBV-induced lymphomagenesis in CBH mice, and suggest potentially important immunologic roles of EBNA3C in vivo.
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MESH Headings
- Animals
- Cell Transformation, Viral/genetics
- Cells, Cultured
- Disease Models, Animal
- Epstein-Barr Virus Infections/complications
- Epstein-Barr Virus Infections/genetics
- Epstein-Barr Virus Nuclear Antigens/genetics
- Fetal Blood/immunology
- HEK293 Cells
- Herpesvirus 4, Human/genetics
- Herpesvirus 4, Human/physiology
- Humans
- Lymphoma, B-Cell/immunology
- Lymphoma, B-Cell/pathology
- Lymphoma, B-Cell/virology
- Mice
- Mice, Inbred NOD
- Mice, Transgenic
- Virus Latency/genetics
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Affiliation(s)
- James C. Romero-Masters
- Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Makoto Ohashi
- Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Reza Djavadian
- Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Mark R. Eichelberg
- Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Mitch Hayes
- Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Jillian A. Bristol
- Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Shidong Ma
- Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Erik A. Ranheim
- Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Jenny Gumperz
- Department of Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Eric C. Johannsen
- Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Shannon C. Kenney
- Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
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Abstract
INTRODUCTION Dysregulated B cell receptor (BCR) signaling has been identified as a potent contributor to tumor survival in B cell non-Hodgkin lymphomas (NHLs). This pathway's emergence as a rational therapeutic target in NHL led to development of BCR-directed agents, including inhibitors of Bruton's tyrosine kinase (BTK), spleen tyrosine kinase (SYK), and phosphatidylinositol 3 kinase (PI3K). Several drugs have become valuable assets in the anti-lymphoma armamentarium. AREAS COVERED We provide an overview of the BCR pathway, its dysregulation in B cell NHL, and the drugs developed to target BCR signaling in lymphoma. Mechanisms, pharmacokinetics, pharmacodynamics, efficacy, and toxicity of currently available BTK, SYK, and PI3K inhibitors are described. EXPERT OPINION While the excellent response rates and favorable toxicity profile of the BTK inhibitor ibrutinib in certain NHL subtypes have propelled it to consideration as frontline therapy in selected populations, additional data and clinical studies are needed before other agents targeting BCR signaling influence clinical practice similarly. PI3K inhibitors remain an option for some relapsed indolent lymphomas and chronic lymphocytic leukemia, but their widespread use may be limited by adverse effects. Future research should include efforts to overcome resistance to BTK inhibitors, combination therapy using BCR-targeted agents, and exploration of novel agents.
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Affiliation(s)
- Kelly Valla
- Winship Cancer Institute of Emory University - Department of Hematology and Medical Oncology, 1365 C Clifton Rd NE, Atlanta, Georgia 30322, United States
| | - Christopher R. Flowers
- Emory University - Winship Cancer Institute, School of Medicine, 1365 Clifton Road, N.E. Building B, Atlanta, Georgia 30322, United States
| | - Jean L. Koff
- Emory University - Winship Cancer Institute, School of Medicine, 1365 Clifton Road, N.E. Building B, Atlanta, Georgia 30322, United States
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50
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Darwiche W, Gubler B, Marolleau JP, Ghamlouch H. Chronic Lymphocytic Leukemia B-Cell Normal Cellular Counterpart: Clues From a Functional Perspective. Front Immunol 2018; 9:683. [PMID: 29670635 PMCID: PMC5893869 DOI: 10.3389/fimmu.2018.00683] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Accepted: 03/20/2018] [Indexed: 12/20/2022] Open
Abstract
Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of small mature-looking CD19+ CD23+ CD5+ B-cells that accumulate in the blood, bone marrow, and lymphoid organs. To date, no consensus has been reached concerning the normal cellular counterpart of CLL B-cells and several B-cell types have been proposed. CLL B-cells have remarkable phenotypic and gene expression profile homogeneity. In recent years, the molecular and cellular biology of CLL has been enriched by seminal insights that are leading to a better understanding of the natural history of the disease. Immunophenotypic and molecular approaches (including immunoglobulin heavy-chain variable gene mutational status, transcriptional and epigenetic profiling) comparing the normal B-cell subset and CLL B-cells provide some new insights into the normal cellular counterpart. Functional characteristics (including activation requirements and propensity for plasma cell differentiation) of CLL B-cells have now been investigated for 50 years. B-cell subsets differ substantially in terms of their functional features. Analysis of shared functional characteristics may reveal similarities between normal B-cell subsets and CLL B-cells, allowing speculative assignment of a normal cellular counterpart for CLL B-cells. In this review, we summarize current data regarding peripheral B-cell differentiation and human B-cell subsets and suggest possibilities for a normal cellular counterpart based on the functional characteristics of CLL B-cells. However, a definitive normal cellular counterpart cannot be attributed on the basis of the available data. We discuss the functional characteristics required for a cell to be logically considered to be the normal counterpart of CLL B-cells.
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Affiliation(s)
- Walaa Darwiche
- EA 4666 Lymphocyte Normal - Pathologique et Cancers, HEMATIM, Université de Picardie Jules Verne, Amiens, France.,Laboratoire d'Hématologie, Centre Hospitalier Universitaire Amiens-Picardie, Amiens, France
| | - Brigitte Gubler
- EA 4666 Lymphocyte Normal - Pathologique et Cancers, HEMATIM, Université de Picardie Jules Verne, Amiens, France.,Laboratoire d'Oncobiologie Moléculaire, Centre Hospitalier Universitaire Amiens-Picardie, Amiens, France
| | - Jean-Pierre Marolleau
- EA 4666 Lymphocyte Normal - Pathologique et Cancers, HEMATIM, Université de Picardie Jules Verne, Amiens, France.,Service d'Hématologie Clinique et Thérapie cellulaire, Centre Hospitalier Universitaire Amiens-Picardie, Amiens, France
| | - Hussein Ghamlouch
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1170, Gustave Roussy, Villejuif, France.,Institut Gustave Roussy, Villejuif, France.,Université Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France
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