HOXA9 Reprograms the Enhancer Landscape to Promote Leukemogenesis

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. [Display omitted] •Leukemogenesis driven by HOXA9 is accompanied by epigenome remodeling•HOXA9 mediates the establishment of de novo enhancers in leukemia cells•HOXA9 interacts with the MLL3/MLL4 histone methyltransferase complex•MLL3/MLL4 complex is required for HOXA9/MEIS1 leukemia in vitro and in vivo 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.