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.
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Acknowledgements
The authors wish to thank Margarita Romero for excellent technical assistance and maintenance of the mouse colony, Dr Eric Brown for providing ATM+/− mice for colony generation and insightful comments on the work, the AFCRI histology core for assistance with tissue paraffin embedding and sectioning, and Dr Priya Aggarwal for assistance with flow cytometry and cytogenetic techniques. This work was supported by a grant from the NIH (CA93237) (JAD).
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Vaites, L., Lian, Z., Lee, E. et al. ATM deficiency augments constitutively nuclear cyclin D1-driven genomic instability and lymphomagenesis. Oncogene 33, 129–133 (2014). https://doi.org/10.1038/onc.2012.577
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DOI: https://doi.org/10.1038/onc.2012.577
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