Chromatin state changes in HOXA9/MEIS1 leukemia cells [ChIP-Seq]

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/ and the histone H3K4 methyltransferase MLL3/MLL4 complex. The HOXA9 function at de novo enhancers is distinct from its physiological role at enhancers during normal hematopoietic development. The MLL3/MLL4 complex physically interacts with HOXA9 and is required both for the active enhancer signatures at de novo enhancers and HOXA9/MEIS1-mediated leukemogenesis. The findings suggest that therapeutic targeting of HOXA9-dependent histone methylation could be an effective therapeutic strategy in acute leukemia associated with HOXA9 over expression.