2. Academic Validation
  3. ATM deficiency promotes development of murine B-cell lymphomas that resemble diffuse large B-cell lymphoma in humans

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.
Karen S Hathcock 1,  Hesed M Padilla-Nash 2,  Jordi Camps 3,  Dong-Mi Shin 4,  Daniel Triner 1,  Arthur L Shaffer 3rd 5,  Robert W Maul 6,  Seth M Steinberg 7,  Patricia J Gearhart 6,  Louis M Staudt 5,  Herbert C Morse 3rd 8,  Thomas Ried 2,  Richard J Hodes 9
Affiliations

Affiliations

  • 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.
PMID: 26400962 DOI: 10.1182/blood-2015-06-654749
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.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15473
    99.76%, IKKβ Inhibitor
    IKK