The transcription factor HIF2 partakes in the differentiation block of acute myeloid leukemia

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 HIF1 alpha and HIF2 alpha, we found that both genes exert oncogenic functions in AML and that HIF2 alpha is a novel regulator of the AML differentiation block. Mechanistically, we found that HIF2 alpha promotes the expression of transcriptional repressors that have been implicated in suppressing AML myeloid differentiation programs. Importantly, we positioned HIF2 alpha under direct transcriptional control by the prodifferentiation agent all-trans retinoic acid (ATRA) and demonstrated that HIF2 alpha blockade cooperates with ATRA to trigger AML cell differentiation. In conclusion, we propose that HIF2 alpha inhibition may open new therapeutic avenues for AML treatment by licensing blasts maturation and leukemia debulking.