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 (NPM1^mut) 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.

作为关键的发育调节因子，HOX 簇基因在正常和恶性造血过程中具有不同且特定的作用。转录因子、表观遗传调节因子、长非编码 RNA 和染色质结构变化之间复杂的相互作用协调着白血病细胞中的 HOX 表达。在这篇综述中，我们总结了 AML 临床亚型中 HOX 调节的分子机制，重点关注占所有 AML 患者三分之一的NPM1 突变 (NPM1 ^{mut ) AML。}虽然 NPM1 突变的白血病启动功能明显依赖于 HOX 活性，但这些 HOX 簇基因上调的患者的良好治疗反应是一个人们知之甚少的矛盾观察。最近的数据证实 FOXM1 是 HOX 活性的抑制因子，也是众所周知的 NPM 结合伴侣，表明 FOXM1 失活可能介导细胞质 NPM 对 HOX 上调的影响。相反，突变 NPM 的残余核部分最近也被证明具有允许 HOX 表达的染色质修饰作用。最近发现 menin-MLL 相互作用是 HOX 依赖性 AML 的一个关键弱点，这推动了 menin 抑制剂的开发，尽管 HOX 基因座的抑制不一致，但这些抑制剂在 NPM1 和 MLL 重排 AML 中具有临床活性。对 AML 中 HOX 的特定环境监管的深入了解可能为针对几种主要 AML 亚型的这一常见漏洞提供坚实的基础。