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ATM deficiency augments constitutively nuclear cyclin D1-driven genomic instability and lymphomagenesis

L P Vaites1, Z Lian1, E K Lee1

  • 11] 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.

Oncogene
|January 16, 2013
PubMed

Insights

Nuclear cyclin D1 retention drives cancer by causing DNA damage and genomic instability. Inactivating ATM in mice accelerates lymphoma development, highlighting a link between DNA repair, cyclin D1, and cancer progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Cyclin D1 deregulation is a key factor in human cancer development.
  • Nuclear cyclin D1 retention during S-phase causes DNA re-replication and genomic instability.
  • This instability is linked to aberrant cyclin D1/CDK4 activity, transcriptional dysregulation, and DNA double-strand break (DSB) induction.

Purpose of the Study:

  • To investigate the synergistic effects of constitutively nuclear cyclin D1 expression and impaired DNA double-strand break (DSB) checkpoint integrity.
  • To determine if inactivating critical checkpoint mediators augments cyclin D1-dependent tumorigenesis in vivo.

Main Methods:

  • Generated and evaluated Ataxia Telangiectasia Mutated (ATM)-deficient mice harboring the Eμ-D1T286A transgene for tumor onset.
  • Compared tumor incidence and chromosomal alterations in Eμ-D1T286A/ATM-/- mice with control cohorts (Eμ-D1T286A and ATM-/-).

Main Results:

  • Mice with both Eμ-D1T286A transgene and ATM deficiency (Eμ-D1T286A/ATM-/-) showed significantly accelerated B- and T-cell lymphoma incidence.
  • Lymphomas in these mice displayed distinct clonal chromosomal alterations, particularly at the c-Myc locus, unlike ATM-/- mice which typically showed Tcrα/δ locus translocations.
  • Nuclear cyclin D1/CDK4 activity drives genomic instability in the absence of ATM function, leading to c-Myc locus alterations and tumor formation.

Conclusions:

  • Nuclear cyclin D1/CDK4 activity is a critical driver of genomic instability when ATM function is compromised.
  • This interplay facilitates the clonal selection of cells with c-Myc locus alterations, promoting neoplastic transformation and tumor development.
  • Findings reveal a complex relationship between cyclin D1, ATM, and c-Myc in cancer pathogenesis.

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