DNA damage response and inflammatory signaling limit the MLL-ENL-induced leukemogenesis in vivo
Jazyk angličtina Země Spojené státy americké Médium print
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
22516260
DOI
10.1016/j.ccr.2012.01.021
PII: S1535-6108(12)00076-1
Knihovny.cz E-zdroje
- MeSH
- DNA vazebné proteiny genetika MeSH
- fúzní onkogenní proteiny genetika MeSH
- genový knockin MeSH
- histonlysin-N-methyltransferasa MeSH
- kofein farmakologie MeSH
- kontrolní body buněčného cyklu genetika MeSH
- leukemie genetika MeSH
- lidé MeSH
- myši MeSH
- nádorová transformace buněk MeSH
- nádorové kmenové buňky patologie MeSH
- poškození DNA * MeSH
- proliferace buněk MeSH
- protoonkogenní protein MLL genetika MeSH
- regulace genové exprese u nádorů MeSH
- signální transdukce MeSH
- transkripční faktory genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- DNA vazebné proteiny MeSH
- fúzní onkogenní proteiny MeSH
- histonlysin-N-methyltransferasa MeSH
- Kmt2a protein, mouse MeSH Prohlížeč
- kofein MeSH
- Mllt1 protein, mouse MeSH Prohlížeč
- protoonkogenní protein MLL MeSH
- transkripční faktory 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.
Citace poskytuje Crossref.org
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GEO
GSE35038
