RNA expression changes in HOXA9/MEIS1 leukemia cells

Aberrant expression of homeobox transcription factor HOXA9 is a central component of the leukemogenic program driven by diverse oncogenes. Here we show that HOXA9 overexpression in myeloid progenitor cells and pro-B cells leads to significant rearrangement of the epigenetic landscape with prominent emergence of cancer specific de novo enhancers. HOXA9 acts as a pioneer factor at the de novo enhancers and is required for recruitment of transcription factor CEBP/a and the histone H3K4 methyltransferase MLL3/MLL4 complex. HOXA9 function at the de novo enhancer is distinct from its physiological role at distal enhancers during normal hematopoietic development. Genetic deletion of MLL3/4 specifically affects the active enhancer signatures at de novo enhancers and inhibits HOXA9/MEIS1-mediated leukemogenesis. Our study reveals a previously uncharacterized role of HOXA9 and the MLL3/4 complex in leukemogenesis and provide mechanistic insights in epigenetic deregulation during malignant transformation. Overall design: RNA-seq for untransformed myeloid progenitors (MP)

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Sun Y, Zhou B, Mao F, Xu J, Miao H, Zou Z, Phuc Khoa LT, Jang Y, Cai S, Witkin M, Koche R, Ge K, Dressler GR, Levine RL, Armstrong SA, Dou Y, Hess JL