Sun, YuqingZhou, BoMao, FengbiaoXu, JingMiao, HongzhiZou, ZhenhuaKhoa, Le Tran PhucJang, YounghoonCai, ShengWitkin, MatthewKoche, RichardGe, KaiDressler, GregoryLevine, Ross L.Armstrong, Scott A.Dou, YaliHess, Jay L.2020-01-032020-01-032018-10-08Sun, Y., Zhou, B., Mao, F., Xu, J., Miao, H., Zou, Z., … Hess, J. L. (2018). HOXA9 Reprograms the Enhancer Landscape to Promote Leukemogenesis. Cancer cell, 34(4), 643–658.e5. doi:10.1016/j.ccell.2018.08.018https://hdl.handle.net/1805/21723Aberrant 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 overexpressionen-USPublisher PolicyHOXA9KMT2MLLAcute leukemiaDe novo enhancerEpigeneticsHistone methylationPioneer factorTranscription factorArticle