The transcription factor HIF2a 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 HIF1a and HIF2a we found that both genes exert oncogenic functions in AML and that HIF2a is a novel regulator of the AML differentiation block. Mechanistically, we found that HIF2a promotes the expression of transcriptional repressors that have been implicated in suppressing AML myeloid differentiation programs. Importantly, we positioned HIF2a under direct transcriptional control by the pro-differentiation agent all-trans retinoic acid (ATRA) and demonstrated that HIF2a blockade cooperates with ATRA to trigger AML cell differentiation. In conclusion, we propose that HIF2a inhibition may open new therapeutic avenues for AML treatment by licensing blasts maturation and leukemia debulking.

SUBMITTER: Dr. Daniela Magliulo 

PROVIDER: S-SCDT-10_15252-EMMM_202317810 | biostudies-other |

REPOSITORIES: biostudies-other