The transcription factor HIF2α partakes in the differentiation block of acute myeloid leukemia

Abstract

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. image Hypoxia‐inducible transcription factor HIF2α contributes to acute myeloid leukemia (AML) pathogenesis by taking part to the molecular network that suppresses differentiation of leukemic blasts along the myeloid lineage. Hypoxia‐inducible factors HIF1α and HIF2α promote leukemia progression in cell and patient‐derived models of established AML. In AML cells, HIF2α regulates a novel gene signature that contains Runx2 and BCL11A and transcriptional repressors implicated in suppressing AML myeloid differentiation programs. HIF2α targeting via gene silencing or pharmacological inhibition triggers a myeloid differentiation program and promotes leukemia debulking. All‐trans retinoid acid induces HIF2α expression via direct activity of RAR proteins. Targeting HIF2α cooperates with ATRA to promote myeloid differentiation.