The transcription factor HIF2α 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 cy...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2023-11-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202317810 |
| _version_ | 1797279666605654016 |
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| author | Daniela Magliulo Matilde Simoni Carolina Caserta Cristina Fracassi Serena Belluschi Kety Giannetti Raffaella Pini Ettore Zapparoli Stefano Beretta Martina Uggè Eleonora Draghi Federico Rossari Nadia Coltella Cristina Tresoldi Marco J Morelli Raffaella Di Micco Bernhard Gentner Luca Vago Rosa Bernardi |
| author_facet | Daniela Magliulo Matilde Simoni Carolina Caserta Cristina Fracassi Serena Belluschi Kety Giannetti Raffaella Pini Ettore Zapparoli Stefano Beretta Martina Uggè Eleonora Draghi Federico Rossari Nadia Coltella Cristina Tresoldi Marco J Morelli Raffaella Di Micco Bernhard Gentner Luca Vago Rosa Bernardi |
| author_sort | Daniela Magliulo |
| collection | DOAJ |
| description | 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 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. |
| first_indexed | 2024-03-07T16:30:17Z |
| format | Article |
| id | doaj.art-2d1702404ed248f580d807aa7c1fabee |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T16:30:17Z |
| publishDate | 2023-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-2d1702404ed248f580d807aa7c1fabee2024-03-03T11:15:45ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-11-011511n/an/a10.15252/emmm.202317810The transcription factor HIF2α partakes in the differentiation block of acute myeloid leukemiaDaniela Magliulo0Matilde Simoni1Carolina Caserta2Cristina Fracassi3Serena Belluschi4Kety Giannetti5Raffaella Pini6Ettore Zapparoli7Stefano Beretta8Martina Uggè9Eleonora Draghi10Federico Rossari11Nadia Coltella12Cristina Tresoldi13Marco J Morelli14Raffaella Di Micco15Bernhard Gentner16Luca Vago17Rosa Bernardi18Division of Experimental Oncology IRCCS San Raffaele Scientific Institute Milan ItalyDivision of Experimental Oncology IRCCS San Raffaele Scientific Institute Milan ItalySan Raffaele Telethon Institute for Gene Therapy (SR‐TIGET) IRCCS San Raffaele Scientific Institute Milan ItalyDivision of Experimental Oncology IRCCS San Raffaele Scientific Institute Milan ItalyVita Salute San Raffaele University School of Medicine Milan ItalySan Raffaele Telethon Institute for Gene Therapy (SR‐TIGET) IRCCS San Raffaele Scientific Institute Milan ItalyCenter for Omics Sciences IRCCS San Raffaele Scientific Institute Milan ItalyCenter for Omics Sciences IRCCS San Raffaele Scientific Institute Milan ItalySan Raffaele Telethon Institute for Gene Therapy (SR‐TIGET) IRCCS San Raffaele Scientific Institute Milan ItalyDivision of Experimental Oncology IRCCS San Raffaele Scientific Institute Milan ItalyUnit of Immunogenetics, Leukemia Genomics and Immunobiology IRCCS San Raffaele Scientific Institute Milan ItalySan Raffaele Telethon Institute for Gene Therapy (SR‐TIGET) IRCCS San Raffaele Scientific Institute Milan ItalySan Raffaele Telethon Institute for Gene Therapy (SR‐TIGET) IRCCS San Raffaele Scientific Institute Milan ItalyUnit of Hematology and Bone Marrow Transplantation IRCCS San Raffaele Scientific Institute Milan ItalyCenter for Omics Sciences IRCCS San Raffaele Scientific Institute Milan ItalySan Raffaele Telethon Institute for Gene Therapy (SR‐TIGET) IRCCS San Raffaele Scientific Institute Milan ItalySan Raffaele Telethon Institute for Gene Therapy (SR‐TIGET) IRCCS San Raffaele Scientific Institute Milan ItalyUnit of Immunogenetics, Leukemia Genomics and Immunobiology IRCCS San Raffaele Scientific Institute Milan ItalyDivision of Experimental Oncology IRCCS San Raffaele Scientific Institute Milan ItalyAbstract 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.https://doi.org/10.15252/emmm.202317810AMLATRAdifferentiation therapyHIF2α |
| spellingShingle | Daniela Magliulo Matilde Simoni Carolina Caserta Cristina Fracassi Serena Belluschi Kety Giannetti Raffaella Pini Ettore Zapparoli Stefano Beretta Martina Uggè Eleonora Draghi Federico Rossari Nadia Coltella Cristina Tresoldi Marco J Morelli Raffaella Di Micco Bernhard Gentner Luca Vago Rosa Bernardi The transcription factor HIF2α partakes in the differentiation block of acute myeloid leukemia EMBO Molecular Medicine AML ATRA differentiation therapy HIF2α |
| title | The transcription factor HIF2α partakes in the differentiation block of acute myeloid leukemia |
| title_full | The transcription factor HIF2α partakes in the differentiation block of acute myeloid leukemia |
| title_fullStr | The transcription factor HIF2α partakes in the differentiation block of acute myeloid leukemia |
| title_full_unstemmed | The transcription factor HIF2α partakes in the differentiation block of acute myeloid leukemia |
| title_short | The transcription factor HIF2α partakes in the differentiation block of acute myeloid leukemia |
| title_sort | transcription factor hif2α partakes in the differentiation block of acute myeloid leukemia |
| topic | AML ATRA differentiation therapy HIF2α |
| url | https://doi.org/10.15252/emmm.202317810 |
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