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| Status |
Public on Aug 10, 2023 |
| Title |
The transcription factor HIF2a partakes in the differentiation blockade of acute myeloid leukaemia [ATAC-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
ATAC-sequencing (ATAC-seq) analysis of 6 samples. Kasumi1 cells were stably transfected with shRNA against HIF2a or a scamble shRNA as control (shCTRL). Each condition was conduced in experimental triplicate.
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| Contributor(s) |
Magliulo D, Giannetti K, Zapparoli E, Di Micco R, Bernardi R |
| Citation(s) |
37807875 |
| |
| Submission date |
May 03, 2022 |
| Last update date |
Nov 09, 2023 |
| Contact name |
Rosa Bernardi |
| E-mail(s) |
bernardi.rosa@hsr.it
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| Organization name |
San Raffaele Scientific Institute
|
| Street address |
via Olgettina 60
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| City |
Milan |
| ZIP/Postal code |
20132 |
| Country |
Italy |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE202107 |
The transcription factor HIF2a partakes in the differentiation blockade of acute myeloid leukaemia |
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| Relations |
| BioProject |
PRJNA834736 |
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