DNA damage response and inflammatory signaling limit the MLL-ENL-induced leukemogenesis in vivo

Cancer Cell. 2012 Apr 17;21(4):517-31. doi: 10.1016/j.ccr.2012.01.021.


Activation of the MLL-ENL-ERtm oncogene initiates aberrant proliferation of myeloid progenitors. Here, we show induction of a fail-safe mechanism mediated by the DNA damage response (DDR) machinery that results in activation of the ATR/ATM-Chk1/Chk2-p53/p21(CIP1) checkpoint and cellular senescence at early stages of cellular transformation caused by a regulatable MLL-ENL-ERtm in mice. Furthermore, we identified the transcription program underlying this intrinsic anticancer barrier, and DDR-induced inflammatory regulators that fine-tune the signaling toward senescence, thereby modulating the fate of MLL-ENL-immortalized cells in a tissue-environment-dependent manner. Our results indicate that DDR is a rate-limiting event for acquisition of stem cell-like properties in MLL-ENL-ERtm-mediated transformation, as experimental inhibition of the barrier accelerated the transition to immature cell states and acute leukemia development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caffeine / pharmacology
  • Cell Cycle Checkpoints / genetics
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • DNA Damage*
  • DNA-Binding Proteins / genetics*
  • Gene Expression Regulation, Neoplastic
  • Gene Knock-In Techniques
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Leukemia / genetics*
  • Mice
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Neoplastic Stem Cells / pathology
  • Oncogene Proteins, Fusion / genetics*
  • Signal Transduction
  • Transcription Factors / genetics*


  • DNA-Binding Proteins
  • Mllt1 protein, mouse
  • Oncogene Proteins, Fusion
  • Transcription Factors
  • Myeloid-Lymphoid Leukemia Protein
  • Caffeine
  • Histone-Lysine N-Methyltransferase
  • Kmt2a protein, mouse

Associated data

  • GEO/GSE35038