ATM deficiency promotes development of murine B-cell lymphomas that resemble diffuse large B-cell lymphoma in humans
- Blood. 2015 Nov 12;126(20):2291-301. doi: 10.1182/blood-2015-06-654749.
- 1. Experimental Immunology Branch.
- 2. Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD;
- 3. 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;
- 4. 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;
- 5. Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD;
- 6. Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Bethesda, MD;
- 7. Biostatistics and Data Management Section, Office of the Clinical Director, National Cancer Institute, National Institutes of Health, Bethesda, MD; and.
- 8. Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
- 9. Experimental Immunology Branch, National Institute on Aging, National Institutes of Health, Bethesda, MD.
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.