Department of Medicine, Division of Hematology/Oncology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA.
O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA.
Adv Exp Med Biol. 2024;1459:405-430. doi: 10.1007/978-3-031-62731-6_18.
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.
HOXA9 是造血过程中的一个重要转录因子（TF），在许多急性髓系白血病（AML）和急性淋巴细胞白血病（ALL）病例中异常表达，是患者预后不良的一个强有力指标。HOXA9 是一种原癌基因，它既是白血病转化所必需的，也是白血病转化所必需的。HOXA9 在白血病中的表达与患者的生存结局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（如 MLL-MENIN-LEDGF 复合物或 DOT1L/KMT4）、转录因子（如 USF1/USF2）和非编码 RNA（如 HOTTIP 和 HOTAIR）在白血病中调节 HOXA9 mRNA 和蛋白。HOXA9 通过其下游靶转录因子（包括 LMO2、抗凋亡 BCL2、SOX4 和受体酪氨酸激酶 FLT3 和 STAT5）调节生存、自我更新和祖细胞周期。这种动态的多层次 HOXA9 调控网络为治疗提供了新的机会，包括针对 DOT1L/KMT4、MENIN、NPM1 和 ENL 蛋白的抑制剂。最近的发现还表明，HOXA9 通过积极抑制髓系分化基因来维持白血病。本章总结了近年来对 HOXA9 介导的白血病发生的生化机制、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的理解进展。
