title: Early B-cell-specific inactivation of ATM synergizes with ectopic CyclinD1 expression to promote pre-germinal center B-cell lymphomas in mice.
abstract: 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.
authors: 1] Institute for Cancer Genetics, College for Physicians and Surgeons, Columbia University, New York, NY, USA [2] Graduate Program for Pathobiology and Molecular Medicine, College for Physicians and Surgeons, Columbia University, New York, NY, USA.
authors: K
authors: K
authors: Yamamoto
authors: Institute for Cancer Genetics, College for Physicians and Surgeons, Columbia University, New York, NY, USA.
authors: B J
authors: BJ
authors: Lee
authors: Institute for Cancer Genetics, College for Physicians and Surgeons, Columbia University, New York, NY, USA.
authors: C
authors: C
authors: Li
authors: Institute for Cancer Genetics, College for Physicians and Surgeons, Columbia University, New York, NY, USA.
authors: R L
authors: RL
authors: Dubois
authors: 1] Centre for Biological Signaling Studies BIOSS, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany [2] Department of Molecular Immunology, Albert-Ludwigs-Universität Freiburg and Max Planck Institute for Immunobiology, Freiburg, Germany.
authors: E
authors: E
authors: Hobeika
authors: Department of Pathology and Cell Biology, College for Physicians and Surgeons, Columbia University, New York, NY, USA.
authors: G
authors: 000000016250048X
authors: G
authors: Bhagat
authors: 1] Institute for Cancer Genetics, College for Physicians and Surgeons, Columbia University, New York, NY, USA [2] Department of Pathology and Cell Biology, College for Physicians and Surgeons, Columbia University, New York, NY, USA [3] Department of Pediatrics, College for Physicians and Surgeons, Columbia University, New York, NY, USA.
authors: S
authors: S
authors: Zha
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000502:physiology*; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D015139:Blotting, Southern; D015153:Blotting, Western; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D042822:Genomic Instability; D018858:Germinal Center / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008231:Lymphopenia / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D051379:Mice; D014407:Tumor Cells, Cultured
chemical_list: D019938:Cyclin D1; D064007:Ataxia Telangiectasia Mutated Proteins