The transcription factor HIF2α partakes in the differentiation block of acute myeloid leukemia.

Autor: Magliulo D; Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy., Simoni M; Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy., Caserta C; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy., Fracassi C; Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy., Belluschi S; Vita Salute San Raffaele University School of Medicine, Milan, Italy., Giannetti K; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy., Pini R; Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy., Zapparoli E; Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy., Beretta S; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy., Uggè M; Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy., Draghi E; Unit of Immunogenetics, Leukemia Genomics and Immunobiology, IRCCS San Raffaele Scientific Institute, Milan, Italy., Rossari F; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.; Vita Salute San Raffaele University School of Medicine, Milan, Italy., Coltella N; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy., Tresoldi C; Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy., Morelli MJ; Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy., Di Micco R; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy., Gentner B; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy., Vago L; Unit of Immunogenetics, Leukemia Genomics and Immunobiology, IRCCS San Raffaele Scientific Institute, Milan, Italy., Bernardi R; Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2023 Nov 08; Vol. 15 (11), pp. e17810. Date of Electronic Publication: 2023 Oct 09.
DOI: 10.15252/emmm.202317810
Abstrakt: 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 HIF1α and HIF2α, we found that both genes exert oncogenic functions in AML and that HIF2α is a novel regulator of the AML differentiation block. Mechanistically, we found that HIF2α promotes the expression of transcriptional repressors that have been implicated in suppressing AML myeloid differentiation programs. Importantly, we positioned HIF2α under direct transcriptional control by the prodifferentiation agent all-trans retinoic acid (ATRA) and demonstrated that HIF2α blockade cooperates with ATRA to trigger AML cell differentiation. In conclusion, we propose that HIF2α inhibition may open new therapeutic avenues for AML treatment by licensing blasts maturation and leukemia debulking.
(© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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