The transcription factor HIF2a partakes in the differentiation blockade of acute myeloid leukaemia [ATAC-seq]

ABSTRACT: Acute myeloid leukemia (AML) is characterized by an accumulation of aberrant myeloid cells arrested at different stages of differentiation. Therapeutic approaches that prompt AML blasts to differentiate represent an attractive opportunity in the landscape of AML therapies, as they aim to induce terminal maturation and leukemia debulking without intensive cytotoxic treatments. In the present study, we investigate the involvement of HIF1 and HIF2 transcription factors in AML pathogenesis, and position HIF2 as a novel regulator of the AML differentiation block. We performed a comparative analysis of HIF1 and HIF2 function in AML cell lines via their inhibition with genetic or pharmacological strategies and found that both factors promote AML proliferation and clonogenicity. Importantly, specific inhibition of HIF2 provokes AML cell differentiation in cell lines and patient-derived xenograft (PDX) models. Mechanistically, we found that HIF2 and EZH2, the catalytic subunit of polycomb repressive complex 2, cooperate at favoring EZH2-mediated deposition of the repressive histone mark H3K27me3 on the regulatory regions of myeloid differentiation genes. Additionally, we demonstrate that HIF2 is positively regulated by the pro-differentiation agent all-trans retinoic acid (ATRA), and its inhibition cooperates with ATRA in triggering AML cell differentiation. In conclusion, we report evidence of a new role of HIF2 in the pathogenesis of AML, by promoting an undifferentiated state via EZH2-mediated epigenetic silencing of myeloid differentiation genes. We propose that HIF2 inhibition may open new therapeutic avenues for AML treatment by licensing AML differentiation and synergizing with ATRA towards leukemia exhaustion.

ORGANISM(S): Homo sapiens

PROVIDER: GSE202106 | GEO | 2023/08/10

REPOSITORIES: GEO