As key developmental regulators, HOX cluster genes have varied and context-specific roles in normal and malignant hematopoiesis. A complex interaction of transcription factors, epigenetic regulators, long non-coding RNAs and chromatin structural changes orchestrate HOX expression in leukemia cells. In this review we summarize molecular mechanisms underlying HOX regulation in clinical subsets of AML, with a focus on NPM1 mutated (NPM1mut) AML comprising a third of all AML patients. While the leukemia initiating function of the NPM1 mutation is clearly dependent on HOX activity, the favorable treatment responses in these patients with upregulation of HOX cluster genes is a poorly understood paradoxical observation. Recent data confirm FOXM1 as a suppressor of HOX activity and a well-known binding partner of NPM suggesting that FOXM1 inactivation may mediate the effect of cytoplasmic NPM on HOX upregulation. Conversely the residual nuclear fraction of mutant NPM has also been recently shown to have chromatin modifying effects permissive to HOX expression. Recent identification of the menin-MLL interaction as a critical vulnerability of HOX-dependent AML has fueled the development of menin inhibitors that are clinically active in NPM1 and MLL rearranged AML despite inconsistent suppression of the HOX locus. Insights into context-specific regulation of HOX in AML may provide a solid foundation for targeting this common vulnerability across several major AML subtypes.
作为关键的发育调控因子，HOX基因簇在正常及恶性造血过程中具有多样化且具环境特异性的功能。转录因子、表观遗传调控因子、长链非编码RNA与染色质结构变化的复杂相互作用共同调控白血病细胞中HOX基因的表达。本综述聚焦于占急性髓系白血病患者总数三分之一的NPM1突变亚型，系统阐述了该疾病临床亚群中HOX基因调控的分子机制。尽管NPM1突变的白血病起始功能明确依赖于HOX活性，但这类患者伴随HOX基因簇上调却出现良好治疗反应的现象，至今仍是未被充分理解的矛盾观察。最新研究证实FOXM1作为HOX活性的抑制因子，其与NPM的相互作用已被广泛认知，提示FOXM1失活可能介导了细胞质NPM对HOX上调的效应。另一方面，近期研究也表明突变型NPM的残余核组分具有促进HOX表达的染色质修饰功能。近期研究识别出menin-MLL相互作用是HOX依赖性急性髓系白血病的关键脆弱点，这推动了menin抑制剂的研发——该类药物在NPM1突变与MLL重排急性髓系白血病中展现出临床活性，尽管其对HOX基因座的抑制效果并不恒定。深入理解HOX基因在急性髓系白血病中的环境特异性调控机制，可能为靶向这一跨越多个主要急性髓系白血病亚型的共同脆弱点奠定坚实基础。
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