HOXA9, an important transcription factor (TF) in hematopoiesis, is aberrantly expressed in numerous cases of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) and is a strong indicator of poor prognosis in patients. HOXA9 is a proto-oncogene which is both sufficient and necessary for leukemia transformation. HOXA9 expression in leukemia correlates with patient survival outcomes and response to therapy. Chromosomal transformations (such as NUP98-HOXA9), mutations, epigenetic dysregulation (e.g., MLL- MENIN -LEDGF complex or DOT1L/KMT4), transcription factors (such as USF1/USF2), and noncoding RNA (such as HOTTIP and HOTAIR) regulate HOXA9 mRNA and protein during leukemia. HOXA9 regulates survival, self-renewal, and progenitor cell cycle through several of its downstream target TFs including LMO2, antiapoptotic BCL2, SOX4, and receptor tyrosine kinase FLT3 and STAT5. This dynamic and multilayered HOXA9 regulome provides new therapeutic opportunities, including inhibitors targeting DOT1L/KMT4, MENIN, NPM1, and ENL proteins. Recent findings also suggest that HOXA9 maintains leukemia by actively repressing myeloid differentiation genes. This chapter summarizes the recent advances understanding biochemical mechanisms underlying HOXA9-mediated leukemogenesis, the clinical significance of its abnormal expression, and pharmacological approaches to treat HOXA9-driven leukemia.
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