title: Mechanisms that can promote peripheral B-cell lymphoma in ATM-deficient mice.
abstract: The Ataxia Telangiectasia-mutated (ATM) kinase senses DNA double-strand breaks (DSB) and facilitates their repair. In humans, ATM deficiency predisposes to B- and T-cell lymphomas, but in mice it leads only to thymic lymphomas. We tested the hypothesis that increased DSB frequency at a cellular oncogene could promote B-cell lymphoma by generating ATM-deficient mice with a V(D)J recombination target (DJβ cassette) within c-myc intron 1 ("DA" mice). We also generated ATM-deficient mice carrying an Eμ-Bcl-2 transgene (AB mice) to test whether enhanced cellular survival could promote B-cell lymphomas. About 30% of DA or AB mice and nearly 100% of mice harboring the combined genotypes (DAB mice) developed mature B-cell lymphomas. In all genotypes, B-cell tumors harbored oncogenic c-myc amplification generated by breakage-fusion-bridge (BFB) from dicentric chromosomes formed through fusion of IgH V(D)J recombination-associated DSBs on chromosome 12 to sequences downstream of c-myc on chromosome 15. AB tumors demonstrate that B lineage cells harboring spontaneous DSBs leading to IgH/c-myc dicentrics are blocked from progressing to B-cell lymphomas by cellular apoptotic responses. DA and DAB tumor translocations were strictly linked to the cassette, but occurred downstream, frequently in a 6-kb region adjacent to c-myc that harbors multiple cryptic V(D)J recombination targets, suggesting that bona fide V(D)J target sequences may activate linked cryptic targets. Our findings indicate that ATM deficiency allows IgH V(D)J recombination DSBs in developing B cells to generate dicentric translocations that, via BFB cycles, lead to c-myc-activating oncogenic translocations and amplifications in mature B cells.
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital; and Department of Genetics, Harvard Medical School, Boston, Massachusetts.
authors.forename: Suprawee
authors.initials: S
authors.lastname: Tepsuporn
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital; and Department of Genetics, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jiazhi
authors.initials: J
authors.lastname: Hu
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital; and Department of Genetics, Harvard Medical School, Boston, Massachusetts alt@enders.tch.harvard.edu Monica.Gostissa2@childrens.harvard.edu.
authors.forename: Monica
authors.initials: M
authors.lastname: Gostissa
authors.affiliation: Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital; and Department of Genetics, Harvard Medical School, Boston, Massachusetts alt@enders.tch.harvard.edu Monica.Gostissa2@childrens.harvard.edu.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D001402:B-Lymphocytes / Q000502:physiology*; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000172:deficiency; D004195:Disease Models, Animal; D015322:Gene Rearrangement, B-Lymphocyte; D006801:Humans; D017578:Immunoglobulin Class Switching; D016393:Lymphoma, B-Cell / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D011995:Recombination, Genetic; D014178:Translocation, Genetic; D060152:V(D)J Recombination / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D016271:Proto-Oncogene Proteins c-myc; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse