One of the defining features of acute myeloid leukemia (AML) is an arrest of myeloid differentiation whose molecular determinants are still poorly defined. Pharmacological removal of the differentiation block contributes to the cure of acute promyelocytic leukemia (APL) in the absence of cytotoxic chemotherapy, but this approach has not yet been translated to non-APL AMLs. Here, by investigating the function of hypoxia-inducible transcription factors HIF1α and HIF2α, we found that both genes exert oncogenic functions in AML and that HIF2α is a novel regulator of the AML differentiation block. Mechanistically, we found that HIF2α promotes the expression of transcriptional repressors that have been implicated in suppressing AML myeloid differentiation programs. Importantly, we positioned HIF2α under direct transcriptional control by the prodifferentiation agent all-trans retinoic acid (ATRA) and demonstrated that HIF2α blockade cooperates with ATRA to trigger AML cell differentiation. In conclusion, we propose that HIF2α inhibition may open new therapeutic avenues for AML treatment by licensing blasts maturation and leukemia debulking.

中文翻译：

---

转录因子HIF2α参与急性髓系白血病的分化阻断

急性髓系白血病 (AML) 的定义特征之一是髓系分化停滞，其分子决定因素仍不清楚。在没有细胞毒性化疗的情况下，药物去除分化阻滞有助于治愈急性早幼粒细胞白血病 (APL)，但这种方法尚未转化为非 APL AML。在这里，通过研究缺氧诱导转录因子 HIF1α 和 HIF2α 的功能，我们发现这两个基因在 AML 中发挥致癌功能，并且 HIF2α 是 AML 分化模块的新型调节因子。从机制上讲，我们发现 HIF2α 促进转录抑制因子的表达，而转录抑制因子与抑制 AML 骨髓分化程序有关。重要的是，我们将 HIF2α 置于促分化剂全反式视黄酸 (ATRA) 的直接转录控制之下，并证明 HIF2α 阻断与 ATRA 协同触发 AML 细胞分化。总之，我们认为 HIF2α 抑制可能通过许可原始细胞成熟和白血病减灭为 AML 治疗开辟新的治疗途径。