Journal
CANCER CELL
Volume 21, Issue 4, Pages 517-531Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2012.01.021
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Funding
- Czech Ministry of Education [NPV2B06077, MSM6198959205, MSM6198959216]
- Czech Grant Agency [GA301/01/0489]
- German research council (DFG) [SL27/7-1]
- Czech Academy of Sciences [IAA501370902]
- Czech Ministry of Health [NS10282-3/2009]
- Danish National Research Foundation
- Danish Cancer Society
- European Commission [CZ.1.05/2.1.00/01.0030]
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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.
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