title: ATM deficiency augments constitutively nuclear cyclin D1-driven genomic instability and lymphomagenesis.
abstract: Cyclin D1 deregulation is implicated in the genesis of multiple human cancers. Importantly, nuclear cyclin D1 retention during S-phase promotes DNA re-replication and subsequent genomic instability, providing a direct correlation between aberrant cyclin D1/CDK4 activity, transcriptional regulation and double strand DNA break (DSB) induction. Together, these molecular events catalyze the genomic instability necessary for neoplastic transformation. Given that replication-associated DNA damage is central to cyclin D1-driven neoplasia, inactivation of critical checkpoint mediators should augment cyclin D1-dependent tumorigenesis in vivo. To interrogate potential synergy between constitutively nuclear cyclin D1 expression and impaired DSB-induced checkpoint integrity, Ataxia Telangiectasia Mutated (ATM)-deficient mice harboring the Eμ-D1T286A transgene were generated and evaluated for tumor onset. Eμ-D1T286A/ATM-/- mice exhibit dramatically accelerated incidence of both B- and T-cell lymphomas relative to Eμ-D1T286A or ATM-/- control cohorts. Lymphomas exhibit clonal chromosomal alterations distinct from ATM-/- mice, which typically acquire translocations involving the Tcrα/δ locus during V(D)J recombination, and instead harbor alterations at the c-Myc locus. Collectively, these findings reveal an intricate relationship wherein nuclear cyclin D1/CDK4 drives genomic instability in the absence of ATM function and clonal selection of cells harboring alterations within the murine c-Myc locus, ultimately facilitating transformation and tumor formation.
authors: 1] The Leonard and Madlyn Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA [2] Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA.
authors: L P
authors: LP
authors: Vaites
authors: 1] The Leonard and Madlyn Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA [2] Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA.
authors: Z
authors: Z
authors: Lian
authors: 1] The Leonard and Madlyn Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA [2] Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA.
authors: E K
authors: EK
authors: Lee
authors: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: B
authors: B
authors: Yin
authors: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: A
authors: A
authors: DeMicco
authors: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: C H
authors: CH
authors: Bassing
authors: 1] The Leonard and Madlyn Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA [2] Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA.
authors: J A
authors: JA
authors: Diehl
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002869:Chromosome Aberrations; D019938:Cyclin D1 / Q000378:metabolism*; D042822:Genomic Instability; D006801:Humans; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D021381:Protein Transport; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D047368:Tumor Burden
chemical_list: C530105:Ccnd1 protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D019938:Cyclin D1; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse