DNA damage response and inflammatory signaling limit the MLL-ENL-induced leukemogenesis in vivo
Language English Country United States Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
22516260
DOI
10.1016/j.ccr.2012.01.021
PII: S1535-6108(12)00076-1
Knihovny.cz E-resources
- MeSH
- DNA-Binding Proteins genetics MeSH
- Oncogene Proteins, Fusion genetics MeSH
- Gene Knock-In Techniques MeSH
- Histone-Lysine N-Methyltransferase MeSH
- Caffeine pharmacology MeSH
- Cell Cycle Checkpoints genetics MeSH
- Leukemia genetics MeSH
- Humans MeSH
- Mice MeSH
- Cell Transformation, Neoplastic MeSH
- Neoplastic Stem Cells pathology MeSH
- DNA Damage * MeSH
- Cell Proliferation MeSH
- Myeloid-Lymphoid Leukemia Protein genetics MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Signal Transduction MeSH
- Transcription Factors genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- DNA-Binding Proteins MeSH
- Oncogene Proteins, Fusion MeSH
- Histone-Lysine N-Methyltransferase MeSH
- Kmt2a protein, mouse MeSH Browser
- Caffeine MeSH
- Mllt1 protein, mouse MeSH Browser
- Myeloid-Lymphoid Leukemia Protein MeSH
- Transcription Factors MeSH
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.
References provided by Crossref.org
Inflammation time-axis in aseptic loosening of total knee arthroplasty: A preliminary study
Regulation and roles of Cdc7 kinase under replication stress
GEO
GSE35038
