Early B-cell-specific inactivation of ATM synergizes with ectopic CyclinD1 expression to promote pre-germinal center B-cell lymphomas in mice

Leukemia. 2015 Jun;29(6):1414-24. doi: 10.1038/leu.2015.41. Epub 2015 Feb 13.


Ataxia telangiectasia-mutated (ATM) kinase is a master regulator of the DNA damage response. ATM is frequently inactivated in human B-cell non-Hodgkin lymphomas, including ~50% of mantle cell lymphomas (MCLs) characterized by ectopic expression of CyclinD1. Here we report that early and robust deletion of ATM in precursor/progenitor B cells causes cell autonomous, clonal mature B-cell lymphomas of both pre- and post-germinal center (GC) origins. Unexpectedly, naive B-cell-specific deletion of ATM is not sufficient to induce lymphomas in mice, highlighting the important tumor suppressor function of ATM in immature B cells. Although EμCyclinD1 is not sufficient to induce lymphomas, EμCyclinD1 accelerates the kinetics and increases the incidence of clonal lymphomas in ATM-deficient B-cells and skews the lymphomas toward pre-GC-derived small lymphocytic neoplasms, sharing morphological features of human MCL. This is in part due to CyclinD1-driven expansion of ATM-deficient naive B cells with genomic instability, which promotes the deletions of additional tumor suppressor genes (i.e. Trp53, Mll2, Rb1 and Cdkn2a). Together these findings define a synergistic function of ATM and CyclinD1 in pre-GC B-cell proliferation and lymphomagenesis and provide a prototypic animal model to study the pathogenesis of human MCL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / physiology*
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology*
  • Blotting, Southern
  • Blotting, Western
  • Cell Proliferation
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism*
  • Flow Cytometry
  • Genomic Instability
  • Germinal Center / metabolism
  • Germinal Center / pathology*
  • Humans
  • Immunoenzyme Techniques
  • In Situ Hybridization, Fluorescence
  • Lymphoma, B-Cell / genetics
  • Lymphoma, B-Cell / metabolism
  • Lymphoma, B-Cell / mortality
  • Lymphoma, B-Cell / pathology*
  • Lymphopenia / genetics
  • Lymphopenia / metabolism
  • Lymphopenia / mortality
  • Lymphopenia / pathology*
  • Mice
  • Tumor Cells, Cultured


  • Cyclin D1
  • Ataxia Telangiectasia Mutated Proteins