Abstract：
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.
摘要：
HOXA9是造血中的重要转录因子(TF),在急性髓性白血病（AML）和急性淋巴细胞白血病（ALL）的许多病例中异常表达，是患者预后不良的有力指标。HOXA9是一种原癌基因，对于白血病转化既足够又必需。白血病中的HOXA9表达与患者生存结果和对治疗的反应相关。染色体转化（如NUP98-HOXA9），突变,表观遗传失调(例如，MLL-MENIN-LEDGF复合物或DOT1L/KMT4），转录因子（如USF1/USF2），非编码RNA（如HOTTIP和HOTAIR）在白血病期间调节HOXA9mRNA和蛋白。HOXA9调节生存，自我更新,和祖细胞周期通过其几个下游靶TFs，包括LMO2，抗凋亡BCL2，SOX4和受体酪氨酸激酶FLT3和STAT5。这种动态的多层HOXA9调节组提供了新的治疗机会，包括靶向DOT1L/KMT4，MENIN，NPM1和ENL蛋白。最近的发现还表明HOXA9通过积极抑制髓样分化基因来维持白血病。本章总结了对HOXA9介导的白血病发生的生化机制的最新进展，其异常表达的临床意义,以及治疗HOXA9驱动的白血病的药理学方法。
