title: ATM deficiency promotes development of murine B-cell lymphomas that resemble diffuse large B-cell lymphoma in humans.
abstract: The serine-threonine kinase ataxia-telangiectasia mutated (ATM) plays a central role in maintaining genomic integrity. In mice, ATM deficiency is exclusively associated with T-cell lymphoma development, whereas B-cell tumors predominate in human ataxia-telangiectasia patients. We demonstrate in this study that when T cells are removed as targets for lymphomagenesis and as mediators of immune surveillance, ATM-deficient mice exclusively develop early-onset immunoglobulin M(+) B-cell lymphomas that do not transplant to immunocompetent mice and that histologically and genetically resemble the activated B cell-like (ABC) subset of human diffuse large B-cell lymphoma (DLBCL). These B-cell lymphomas show considerable chromosomal instability and a recurrent genomic amplification of a 4.48-Mb region on chromosome 18 that contains Malt1 and is orthologous to a region similarly amplified in human ABC DLBCL. Of importance, amplification of Malt1 in these lymphomas correlates with their dependence on nuclear factor (NF)-κB, MALT1, and B-cell receptor (BCR) signaling for survival, paralleling human ABC DLBCL. Further, like some human ABC DLBCLs, these mouse B-cell lymphomas also exhibit constitutive BCR-dependent NF-κB activation. This study reveals that ATM protects against development of B-cell lymphomas that model human ABC DLBCL and identifies a potential role for T cells in preventing the emergence of these tumors.
authors.affiliation: Experimental Immunology Branch.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Hathcock
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Hesed M
authors.initials: HM
authors.lastname: Padilla-Nash
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; Gastrointestinal and Pancreatic Oncology Group, Institut D'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain;
authors.forename: Jordi
authors.initials: J
authors.lastname: Camps
authors.affiliation: Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; Department of Food and Nutrition, Seoul National University, Seoul, Korea;
authors.forename: Dong-Mi
authors.initials: DM
authors.lastname: Shin
authors.affiliation: Experimental Immunology Branch.
authors.forename: Daniel
authors.initials: D
authors.lastname: Triner
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Arthur L
authors.identifier: http://orcid.org/0000-0002-2173-229X
authors.initials: AL
authors.lastname: Shaffer
authors.affiliation: Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Bethesda, MD;
authors.forename: Robert W
authors.initials: RW
authors.lastname: Maul
authors.affiliation: Biostatistics and Data Management Section, Office of the Clinical Director, National Cancer Institute, National Institutes of Health, Bethesda, MD; and.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.affiliation: Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Bethesda, MD;
authors.forename: Patricia J
authors.identifier: http://orcid.org/0000-0003-1975-4737
authors.initials: PJ
authors.lastname: Gearhart
authors.affiliation: Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
authors.affiliation: Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
authors.forename: Herbert C
authors.identifier: http://orcid.org/0000-0002-9331-3705
authors.initials: HC
authors.lastname: Morse
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.affiliation: Experimental Immunology Branch, National Institute on Aging, National Institutes of Health, Bethesda, MD.
authors.forename: Richard J
authors.identifier: http://orcid.org/0000-0002-8142-5742
authors.initials: RJ
authors.lastname: Hodes
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency* / Q000276:immunology; D020169:Caspases / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D043171:Chromosomal Instability / Q000276:immunology; D056426:Genetic Loci / Q000276:immunology; D006801:Humans; D007157:Immunologic Surveillance; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000276:immunology
chemical_list: D016328:NF-kappa B; D009363:Neoplasm Proteins; D011947:Receptors, Antigen, B-Cell; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D020169:Caspases; C400109:MALT1 protein, human; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein