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CDK4 deficiency promotes genomic instability and enhances Myc-driven lymphomagenesis

Academic Article
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Overview

authors

  • Lu, Y.
  • Wu, Y.
  • Feng, X.
  • Shen, R.
  • Wang, J. H.
  • Fallahi, M.
  • Li, W.
  • Yang, C.
  • Hankey, W.
  • Zhao, W.
  • Ganju, R. K.
  • Li, M. O.
  • Cleveland, John
  • Zou, X.

publication date

  • April 2014

journal

  • Journal of Clinical Investigation  Journal

abstract

  • The G1 kinase CDK4 is amplified or overexpressed in some human tumors and promotes tumorigenesis by inhibiting known tumor suppressors. Here, we report that CDK4 deficiency markedly accelerated lymphoma development in the Eμ-Myc transgenic mouse model of B lymphoma and that silencing or loss of CDK4 augmented the tumorigenic potential of Myc-driven mouse and human B cell lymphoma in transplant models. Accelerated disease in CDK4-deficient Eμ-Myc transgenic mice was associated with rampant genomic instability that was provoked by dysregulation of a FOXO1/RAG1/RAG2 pathway. Specifically, CDK4 phosphorylated and inactivated FOXO1, which prevented FOXO1-dependent induction of Rag1 and Rag2 transcription. CDK4-deficient Eμ-Myc B cells had high levels of the active form of FOXO1 and elevated RAG1 and RAG2. Furthermore, overexpression of RAG1 and RAG2 accelerated lymphoma development in a transplant model, with RAG1/2-expressing tumors exhibiting hallmarks of genomic instability. Evaluation of human tumor samples revealed that CDK4 expression was markedly suppressed, while FOXO1 expression was elevated, in several subtypes of human non-Hodgkin B cell lymphoma. Collectively, these findings establish a context-specific tumor suppressor function for CDK4 that prevents genomic instability, which contributes to B cell lymphoma. Furthermore, our data suggest that targeting CDK4 may increase the risk for the development and/or progression of lymphoma.

subject areas

  • Animals
  • Cyclin-Dependent Kinase 4
  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Genes, myc
  • Genomic Instability
  • Heterografts
  • Homeodomain Proteins
  • Humans
  • Lymphoma, B-Cell
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-myc
  • Signal Transduction
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Identity

PubMed Central ID

  • PMC3973114

International Standard Serial Number (ISSN)

  • 0021-9738

Digital Object Identifier (DOI)

  • 10.1172/jci63139

PubMed ID

  • 24614102
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Additional Document Info

start page

  • 1672

end page

  • 1684

volume

  • 124

issue

  • 4

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