HOXA9 reprograms the enhancer landscape to promote leukemogenesis Journal Article
| Authors: | Sun, Y.; Zhou, B.; Mao, F.; Xu, J.; Miao, H.; Zou, Z.; Phuc Khoa, L. T.; Jang, Y.; Cai, S.; Witkin, M.; Koche, R.; Ge, K.; Dressler, G. R.; Levine, R. L.; Armstrong, S. A.; Dou, Y.; Hess, J. L. |
| Article Title: | HOXA9 reprograms the enhancer landscape to promote leukemogenesis |
| 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. Sun et al. show that HOXA9 overexpression in myeloid and B progenitor cells induces emergence of leukemia-specific enhancers by recruiting CEBPα and the MLL3/MLL4 complex, leading to activation of an ectopic embryonic gene program. Genetic deletion of MLL3/MLL4 inhibits HOXA9/MEIS1-mediated leukemogenesis. © 2018 Elsevier Inc. |
| Keywords: | transcription factor; acute leukemia; epigenetics; histone methylation; mll; hoxa9; pioneer factor; de novo enhancer; kmt2 |
| Journal Title: | Cancer Cell |
| Volume: | 34 |
| Issue: | 4 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2018-10-08 |
| Start Page: | 643 |
| End Page: | 658.e5 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2018.08.018 |
| PUBMED: | 30270123 |
| PROVIDER: | scopus |
| PMCID: | PMC6179449 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 November 2018 -- Source: Scopus |
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