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Biological Effects of BET Inhibition by OTX015 (MK-8628) and JQ1 in NPM1-Mutated (NPM1c) Acute Myeloid Leukemia (AML)

BET inhibitors (BETi) including OTX015 (MK-8628) and JQ1 demonstrated antileukemic activity including NPM1c AML cells. Nevertheless, the biological consequences of BETi in NPM1c AML were not fully investigated. Even if of better prognosis AML patients with NPM1c may relapse and treatment remains dif...

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Autores principales: Djamai, Hanane, Berrou, Jeannig, Dupont, Mélanie, Coudé, Marie-Magdelaine, Delord, Marc, Clappier, Emmanuelle, Marceau-Renaut, Alice, Kaci, Anna, Raffoux, Emmanuel, Itzykson, Raphaël, Berthier, Caroline, Wu, Hsin-Chieh, Hleihel, Rita, Bazarbachi, Ali, de Thé, Hugues, Baruchel, André, Gardin, Claude, Dombret, Hervé, Braun, Thorsten
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8615962/
https://www.ncbi.nlm.nih.gov/pubmed/34829934
http://dx.doi.org/10.3390/biomedicines9111704
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author Djamai, Hanane
Berrou, Jeannig
Dupont, Mélanie
Coudé, Marie-Magdelaine
Delord, Marc
Clappier, Emmanuelle
Marceau-Renaut, Alice
Kaci, Anna
Raffoux, Emmanuel
Itzykson, Raphaël
Berthier, Caroline
Wu, Hsin-Chieh
Hleihel, Rita
Bazarbachi, Ali
de Thé, Hugues
Baruchel, André
Gardin, Claude
Dombret, Hervé
Braun, Thorsten
author_facet Djamai, Hanane
Berrou, Jeannig
Dupont, Mélanie
Coudé, Marie-Magdelaine
Delord, Marc
Clappier, Emmanuelle
Marceau-Renaut, Alice
Kaci, Anna
Raffoux, Emmanuel
Itzykson, Raphaël
Berthier, Caroline
Wu, Hsin-Chieh
Hleihel, Rita
Bazarbachi, Ali
de Thé, Hugues
Baruchel, André
Gardin, Claude
Dombret, Hervé
Braun, Thorsten
author_sort Djamai, Hanane
collection PubMed
description BET inhibitors (BETi) including OTX015 (MK-8628) and JQ1 demonstrated antileukemic activity including NPM1c AML cells. Nevertheless, the biological consequences of BETi in NPM1c AML were not fully investigated. Even if of better prognosis AML patients with NPM1c may relapse and treatment remains difficult. Differentiation-based therapy by all trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) demonstrated activity in NPM1c AML. We found that BETi, similar to ATO + ATRA, induced differentiation and apoptosis which was TP53 independent in the NPM1c cell line OCI-AML3 and primary cells. Furthermore, BETi induced proteasome-dependent degradation of NPM1c. BETi degraded NPM1c in the cytosol while BRD4 is degraded in the nucleus which suggests that restoration of the NPM1/BRD4 equilibrium in the nucleus of NPM1c cells is essential for the efficacy of BETi. While ATO + ATRA had significant biological activity in NPM1c IMS-M2 cell line, those cells were resistant to BETi. Gene profiling revealed that IMS-M2 cells probably resist to BETi by upregulation of LSC pathways independently of the downregulation of a core BET-responsive transcriptional program. ATO + ATRA downregulated a NPM1c specific HOX gene signature while anti-leukemic effects of BETi appear HOX gene independent. Our preclinical results encourage clinical testing of BETi in NPM1c AML patients.
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spelling pubmed-86159622021-11-26 Biological Effects of BET Inhibition by OTX015 (MK-8628) and JQ1 in NPM1-Mutated (NPM1c) Acute Myeloid Leukemia (AML) Djamai, Hanane Berrou, Jeannig Dupont, Mélanie Coudé, Marie-Magdelaine Delord, Marc Clappier, Emmanuelle Marceau-Renaut, Alice Kaci, Anna Raffoux, Emmanuel Itzykson, Raphaël Berthier, Caroline Wu, Hsin-Chieh Hleihel, Rita Bazarbachi, Ali de Thé, Hugues Baruchel, André Gardin, Claude Dombret, Hervé Braun, Thorsten Biomedicines Article BET inhibitors (BETi) including OTX015 (MK-8628) and JQ1 demonstrated antileukemic activity including NPM1c AML cells. Nevertheless, the biological consequences of BETi in NPM1c AML were not fully investigated. Even if of better prognosis AML patients with NPM1c may relapse and treatment remains difficult. Differentiation-based therapy by all trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) demonstrated activity in NPM1c AML. We found that BETi, similar to ATO + ATRA, induced differentiation and apoptosis which was TP53 independent in the NPM1c cell line OCI-AML3 and primary cells. Furthermore, BETi induced proteasome-dependent degradation of NPM1c. BETi degraded NPM1c in the cytosol while BRD4 is degraded in the nucleus which suggests that restoration of the NPM1/BRD4 equilibrium in the nucleus of NPM1c cells is essential for the efficacy of BETi. While ATO + ATRA had significant biological activity in NPM1c IMS-M2 cell line, those cells were resistant to BETi. Gene profiling revealed that IMS-M2 cells probably resist to BETi by upregulation of LSC pathways independently of the downregulation of a core BET-responsive transcriptional program. ATO + ATRA downregulated a NPM1c specific HOX gene signature while anti-leukemic effects of BETi appear HOX gene independent. Our preclinical results encourage clinical testing of BETi in NPM1c AML patients. MDPI 2021-11-17 /pmc/articles/PMC8615962/ /pubmed/34829934 http://dx.doi.org/10.3390/biomedicines9111704 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Djamai, Hanane
Berrou, Jeannig
Dupont, Mélanie
Coudé, Marie-Magdelaine
Delord, Marc
Clappier, Emmanuelle
Marceau-Renaut, Alice
Kaci, Anna
Raffoux, Emmanuel
Itzykson, Raphaël
Berthier, Caroline
Wu, Hsin-Chieh
Hleihel, Rita
Bazarbachi, Ali
de Thé, Hugues
Baruchel, André
Gardin, Claude
Dombret, Hervé
Braun, Thorsten
Biological Effects of BET Inhibition by OTX015 (MK-8628) and JQ1 in NPM1-Mutated (NPM1c) Acute Myeloid Leukemia (AML)
title Biological Effects of BET Inhibition by OTX015 (MK-8628) and JQ1 in NPM1-Mutated (NPM1c) Acute Myeloid Leukemia (AML)
title_full Biological Effects of BET Inhibition by OTX015 (MK-8628) and JQ1 in NPM1-Mutated (NPM1c) Acute Myeloid Leukemia (AML)
title_fullStr Biological Effects of BET Inhibition by OTX015 (MK-8628) and JQ1 in NPM1-Mutated (NPM1c) Acute Myeloid Leukemia (AML)
title_full_unstemmed Biological Effects of BET Inhibition by OTX015 (MK-8628) and JQ1 in NPM1-Mutated (NPM1c) Acute Myeloid Leukemia (AML)
title_short Biological Effects of BET Inhibition by OTX015 (MK-8628) and JQ1 in NPM1-Mutated (NPM1c) Acute Myeloid Leukemia (AML)
title_sort biological effects of bet inhibition by otx015 (mk-8628) and jq1 in npm1-mutated (npm1c) acute myeloid leukemia (aml)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8615962/
https://www.ncbi.nlm.nih.gov/pubmed/34829934
http://dx.doi.org/10.3390/biomedicines9111704
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