| Literature DB >> 30270123 |
Yuqing Sun1, Bo Zhou1, Fengbiao Mao1, Jing Xu1, Hongzhi Miao1, Zhenhua Zou1, Le Tran Phuc Khoa1, Younghoon Jang2, Sheng Cai3, Matthew Witkin3, Richard Koche3, Kai Ge2, Gregory R Dressler1, Ross L Levine3, Scott A Armstrong4, Yali Dou5, Jay L Hess6.
Abstract
Aberrant expression of HOXA9 is a prominent feature of acute leukemia driven by diverse oncogenes. Here we show that HOXA9 overexpression in myeloid and B progenitor cells leads to significant enhancer reorganizations with prominent emergence of leukemia-specific de novo enhancers. Alterations in the enhancer landscape lead to activation of an ectopic embryonic gene program. We show that HOXA9 functions as a pioneer factor at de novo enhancers and recruits CEBPα and the MLL3/MLL4 complex. Genetic deletion of MLL3/MLL4 blocks histone H3K4 methylation at de novo enhancers and inhibits HOXA9/MEIS1-mediated leukemogenesis in vivo. These results suggest that therapeutic targeting of HOXA9-dependent enhancer reorganization can be an effective therapeutic strategy in acute leukemia with HOXA9 overexpression.Entities:
Keywords: HOXA9; KMT2; MLL; acute leukemia; de novo enhancer; epigenetics; histone methylation; pioneer factor; transcription factor
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Year: 2018 PMID： 30270123 PMCID： PMC6179449 DOI： 10.1016/j.ccell.2018.08.018
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743