Similar Datasets
Project description: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.
2023-08-10 | GSE202106 | GEO
Project description: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 HIF1a and HIF2a transcription factors in AML pathogenesis, and position HIF2a as a novel regulator of the AML differentiation block. We performed a comparative analysis of HIF1a and HIF2a 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 HIF2a provokes AML cell differentiation in cell lines and patient-derived xenograft (PDX) models. Additionally, we demonstrate that HIF2a 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 HIF2a in the pathogenesis of AML, and we propose that HIF2a inhibition may open new therapeutic avenues for AML treatment by licensing AML differentiation and synergizing with ATRA towards leukemia exhaustion.
2023-08-10 | GSE228757 | GEO
Project description: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.
2023-08-10 | GSE175757 | GEO
Project description: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.
| S-SCDT-10_15252-EMMM_202317810 | biostudies-other
Project description:The transcription factor HIF2a partakes in the differentiation blockade of acute myeloid leukaemia
| PRJNA834728 | ENA
Project description:The transcription factor HIF2a partakes in the differentiation blockade of acute myeloid leukaemia [RNA-Seq]
| PRJNA733489 | ENA
Project description:The transcription factor HIF2a partakes in the differentiation blockade of acute myeloid leukaemia [ATAC-seq]
| PRJNA834736 | ENA
Project description:The transcription factor HIF2a partakes in the differentiation blockade of acute myeloid leukaemia [ChIP-seq]
| PRJNA951428 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-12-04 | GSE162398 | GEO
Project description:For several decades, few substantial therapeutic advances have been made for patients with acute myeloid leukaemia. However, since 2017 unprecedented growth has been seen in the number of drugs available for the treatment of acute myeloid leukaemia, with several new drugs receiving regulatory approval. In addition to advancing our therapeutic armamentarium, an increased understanding of the biology and genomic architecture of acute myeloid leukaemia has led to refined risk assessment of this disease, with consensus risk stratification guidelines now incorporating a growing number of recurrent molecular aberrations that aid in the selection of risk-adapted management strategies. Despite this promising recent progress, the outcomes of patients with acute myeloid leukaemia remain unsatisfactory, with more than half of patients ultimately dying from their disease. Enrolment of patients into clinical trials that evaluate novel drugs and rational combination therapies is imperative to continuing this progress and further improving the outcomes of patients with acute myeloid leukaemia.
| S-EPMC10230947 | biostudies-literature