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 <i>NPM1c</i> AML cells. Nevertheless, the biological consequences of BETi in <i>NPM1c</i> AML were not fully investigated. Even if of better prognosis AML patients with <i...

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Autores principales:	Hanane Djamai, Jeannig Berrou, Mélanie Dupont, Marie-Magdelaine Coudé, Marc Delord, Emmanuelle Clappier, Alice Marceau-Renaut, Anna Kaci, Emmanuel Raffoux, Raphaël Itzykson, Caroline Berthier, Hsin-Chieh Wu, Rita Hleihel, Ali Bazarbachi, Hugues de Thé, André Baruchel, Claude Gardin, Hervé Dombret, Thorsten Braun
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	BET inhibitors OTX015 (MK-8628) JQ1 ATRA ATO <i>HOX</i> genes Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/52d5e94b12ce456bbf18b65e4c1fbdfe
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spelling	oai:doaj.org-article:52d5e94b12ce456bbf18b65e4c1fbdfe2021-11-25T16:51:01ZBiological Effects of BET Inhibition by OTX015 (MK-8628) and JQ1 in NPM1-Mutated (NPM1c) Acute Myeloid Leukemia (AML)10.3390/biomedicines91117042227-9059https://doaj.org/article/52d5e94b12ce456bbf18b65e4c1fbdfe2021-11-01T00:00:00Zhttps://www.mdpi.com/2227-9059/9/11/1704https://doaj.org/toc/2227-9059BET inhibitors (BETi) including OTX015 (MK-8628) and JQ1 demonstrated antileukemic activity including <i>NPM1c</i> AML cells. Nevertheless, the biological consequences of BETi in <i>NPM1c</i> AML were not fully investigated. Even if of better prognosis AML patients with <i>NPM1c</i> may relapse and treatment remains difficult. Differentiation-based therapy by all trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) demonstrated activity in <i>NPM1c</i> AML. We found that BETi, similar to ATO + ATRA, induced differentiation and apoptosis which was <i>TP53</i> independent in the <i>NPM1c</i> 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 <i>NPM1c</i> cells is essential for the efficacy of BETi. While ATO + ATRA had significant biological activity in <i>NPM1c</i> 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 <i>NPM1c</i> specific <i>HOX</i> gene signature while anti-leukemic effects of BETi appear <i>HOX</i> gene independent. Our preclinical results encourage clinical testing of BETi in <i>NPM1c</i> AML patients.Hanane DjamaiJeannig BerrouMélanie DupontMarie-Magdelaine CoudéMarc DelordEmmanuelle ClappierAlice Marceau-RenautAnna KaciEmmanuel RaffouxRaphaël ItzyksonCaroline BerthierHsin-Chieh WuRita HleihelAli BazarbachiHugues de ThéAndré BaruchelClaude GardinHervé DombretThorsten BraunMDPI AGarticleBET inhibitorsOTX015 (MK-8628)JQ1ATRAATO<i>HOX</i> genesBiology (General)QH301-705.5ENBiomedicines, Vol 9, Iss 1704, p 1704 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	BET inhibitors OTX015 (MK-8628) JQ1 ATRA ATO <i>HOX</i> genes Biology (General) QH301-705.5
spellingShingle	BET inhibitors OTX015 (MK-8628) JQ1 ATRA ATO <i>HOX</i> genes Biology (General) QH301-705.5 Hanane Djamai Jeannig Berrou Mélanie Dupont Marie-Magdelaine Coudé Marc Delord Emmanuelle Clappier Alice Marceau-Renaut Anna Kaci Emmanuel Raffoux Raphaël Itzykson Caroline Berthier Hsin-Chieh Wu Rita Hleihel Ali Bazarbachi Hugues de Thé André Baruchel Claude Gardin Hervé Dombret Thorsten Braun Biological Effects of BET Inhibition by OTX015 (MK-8628) and JQ1 in NPM1-Mutated (NPM1c) Acute Myeloid Leukemia (AML)
description	BET inhibitors (BETi) including OTX015 (MK-8628) and JQ1 demonstrated antileukemic activity including <i>NPM1c</i> AML cells. Nevertheless, the biological consequences of BETi in <i>NPM1c</i> AML were not fully investigated. Even if of better prognosis AML patients with <i>NPM1c</i> may relapse and treatment remains difficult. Differentiation-based therapy by all trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) demonstrated activity in <i>NPM1c</i> AML. We found that BETi, similar to ATO + ATRA, induced differentiation and apoptosis which was <i>TP53</i> independent in the <i>NPM1c</i> 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 <i>NPM1c</i> cells is essential for the efficacy of BETi. While ATO + ATRA had significant biological activity in <i>NPM1c</i> 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 <i>NPM1c</i> specific <i>HOX</i> gene signature while anti-leukemic effects of BETi appear <i>HOX</i> gene independent. Our preclinical results encourage clinical testing of BETi in <i>NPM1c</i> AML patients.
format	article
author	Hanane Djamai Jeannig Berrou Mélanie Dupont Marie-Magdelaine Coudé Marc Delord Emmanuelle Clappier Alice Marceau-Renaut Anna Kaci Emmanuel Raffoux Raphaël Itzykson Caroline Berthier Hsin-Chieh Wu Rita Hleihel Ali Bazarbachi Hugues de Thé André Baruchel Claude Gardin Hervé Dombret Thorsten Braun
author_facet	Hanane Djamai Jeannig Berrou Mélanie Dupont Marie-Magdelaine Coudé Marc Delord Emmanuelle Clappier Alice Marceau-Renaut Anna Kaci Emmanuel Raffoux Raphaël Itzykson Caroline Berthier Hsin-Chieh Wu Rita Hleihel Ali Bazarbachi Hugues de Thé André Baruchel Claude Gardin Hervé Dombret Thorsten Braun
author_sort	Hanane Djamai
title	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_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_sort	biological effects of bet inhibition by otx015 (mk-8628) and jq1 in npm1-mutated (npm1c) acute myeloid leukemia (aml)
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/52d5e94b12ce456bbf18b65e4c1fbdfe
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Biological Effects of BET Inhibition by OTX015 (MK-8628) and JQ1 in NPM1-Mutated (NPM1c) Acute Myeloid Leukemia (AML)

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