THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors

Autores
Cayrol, Maria Florencia; Praditsuktavorn, Pannee; Fernando, Tharu M.; Kwiatkowski, Nicholas; Marullo, Rosella; Calvo Vidal, M. Nieves; Phillip, Jude; Pera, Benet; Yang, Shao Ning; Takpradit, Kaipol; Roman, Lidia; Gaudiano, Marcello; Crescenzo, Ramona; Ruan, Jia; Inghirami, Giorgio; Zhang, Tinghu; Cremaschi, Graciela Alicia; Gray, Nathanael S.; Cerchietti, Leandro
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Peripheral T-cell lymphomas (PTCL) are aggressive diseases with poor response to chemotherapy and dismal survival. Identification of effective strategies to target PTCL biology represents an urgent need. Here we report that PTCL are sensitive to transcription-targeting drugs, and, in particular, to THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7). The STAT-signalling pathway is highly vulnerable to THZ1 even in PTCL cells that carry the activating STAT3 mutation Y640F. In mutant cells, CDK7 inhibition decreases STAT3 chromatin binding and expression of highly transcribed target genes like MYC, PIM1, MCL1, CD30, IL2RA, CDC25A and IL4R. In surviving cells, THZ1 decreases the expression of STAT-regulated anti-apoptotic BH3 family members MCL1 and BCL-XL sensitizing PTCL cells to BH3 mimetic drugs. Accordingly, the combination of THZ1 and the BH3 mimetic obatoclax improves lymphoma growth control in a primary PTCL ex vivo culture and in two STAT3-mutant PTCL xenografts, delineating a potential targeted agent-based therapeutic option for these patients.
Fil: Cayrol, Maria Florencia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina. Cornell University; Estados Unidos
Fil: Praditsuktavorn, Pannee. Cornell University; Estados Unidos
Fil: Fernando, Tharu M.. Cornell University; Estados Unidos
Fil: Kwiatkowski, Nicholas. Harvard Medical School; Estados Unidos
Fil: Marullo, Rosella. Cornell University; Estados Unidos
Fil: Calvo Vidal, M. Nieves. Cornell University; Estados Unidos
Fil: Phillip, Jude. Cornell University; Estados Unidos
Fil: Pera, Benet. Cornell University; Estados Unidos
Fil: Yang, Shao Ning. Cornell University; Estados Unidos
Fil: Takpradit, Kaipol. Cornell University; Estados Unidos
Fil: Roman, Lidia. Cornell University; Estados Unidos
Fil: Gaudiano, Marcello. Cornell University; Estados Unidos
Fil: Crescenzo, Ramona. Cornell University; Estados Unidos
Fil: Ruan, Jia. Cornell University; Estados Unidos
Fil: Inghirami, Giorgio. Cornell University; Estados Unidos
Fil: Zhang, Tinghu. Harvard Medical School; Estados Unidos
Fil: Cremaschi, Graciela Alicia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Gray, Nathanael S.. Harvard Medical School; Estados Unidos
Fil: Cerchietti, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Cornell University; Estados Unidos
Materia
Cdk7
Bcl2
T Cell Lymphoma
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/55957
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/55957
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitorsCayrol, Maria FlorenciaPraditsuktavorn, PanneeFernando, Tharu M.Kwiatkowski, NicholasMarullo, RosellaCalvo Vidal, M. NievesPhillip, JudePera, BenetYang, Shao NingTakpradit, KaipolRoman, LidiaGaudiano, MarcelloCrescenzo, RamonaRuan, JiaInghirami, GiorgioZhang, TinghuCremaschi, Graciela AliciaGray, Nathanael S.Cerchietti, LeandroCdk7Bcl2T Cell Lymphomahttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Peripheral T-cell lymphomas (PTCL) are aggressive diseases with poor response to chemotherapy and dismal survival. Identification of effective strategies to target PTCL biology represents an urgent need. Here we report that PTCL are sensitive to transcription-targeting drugs, and, in particular, to THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7). The STAT-signalling pathway is highly vulnerable to THZ1 even in PTCL cells that carry the activating STAT3 mutation Y640F. In mutant cells, CDK7 inhibition decreases STAT3 chromatin binding and expression of highly transcribed target genes like MYC, PIM1, MCL1, CD30, IL2RA, CDC25A and IL4R. In surviving cells, THZ1 decreases the expression of STAT-regulated anti-apoptotic BH3 family members MCL1 and BCL-XL sensitizing PTCL cells to BH3 mimetic drugs. Accordingly, the combination of THZ1 and the BH3 mimetic obatoclax improves lymphoma growth control in a primary PTCL ex vivo culture and in two STAT3-mutant PTCL xenografts, delineating a potential targeted agent-based therapeutic option for these patients.Fil: Cayrol, Maria Florencia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina. Cornell University; Estados UnidosFil: Praditsuktavorn, Pannee. Cornell University; Estados UnidosFil: Fernando, Tharu M.. Cornell University; Estados UnidosFil: Kwiatkowski, Nicholas. Harvard Medical School; Estados UnidosFil: Marullo, Rosella. Cornell University; Estados UnidosFil: Calvo Vidal, M. Nieves. Cornell University; Estados UnidosFil: Phillip, Jude. Cornell University; Estados UnidosFil: Pera, Benet. Cornell University; Estados UnidosFil: Yang, Shao Ning. Cornell University; Estados UnidosFil: Takpradit, Kaipol. Cornell University; Estados UnidosFil: Roman, Lidia. Cornell University; Estados UnidosFil: Gaudiano, Marcello. Cornell University; Estados UnidosFil: Crescenzo, Ramona. Cornell University; Estados UnidosFil: Ruan, Jia. Cornell University; Estados UnidosFil: Inghirami, Giorgio. Cornell University; Estados UnidosFil: Zhang, Tinghu. Harvard Medical School; Estados UnidosFil: Cremaschi, Graciela Alicia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Gray, Nathanael S.. Harvard Medical School; Estados UnidosFil: Cerchietti, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Cornell University; Estados UnidosNature2017-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/55957Cayrol, Maria Florencia; Praditsuktavorn, Pannee; Fernando, Tharu M.; Kwiatkowski, Nicholas; Marullo, Rosella; et al.; THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors; Nature; Nature Communications; 8; 1-2017; 1-112041-1723CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/ncomms14290info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/ncomms14290info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:20:46Zoai:ri.conicet.gov.ar:11336/55957instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:20:46.733CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors
title THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors
spellingShingle THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors
Cayrol, Maria Florencia
Cdk7
Bcl2
T Cell Lymphoma
title_short THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors
title_full THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors
title_fullStr THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors
title_full_unstemmed THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors
title_sort THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors
dc.creator.none.fl_str_mv Cayrol, Maria Florencia
Praditsuktavorn, Pannee
Fernando, Tharu M.
Kwiatkowski, Nicholas
Marullo, Rosella
Calvo Vidal, M. Nieves
Phillip, Jude
Pera, Benet
Yang, Shao Ning
Takpradit, Kaipol
Roman, Lidia
Gaudiano, Marcello
Crescenzo, Ramona
Ruan, Jia
Inghirami, Giorgio
Zhang, Tinghu
Cremaschi, Graciela Alicia
Gray, Nathanael S.
Cerchietti, Leandro
author Cayrol, Maria Florencia
author_facet Cayrol, Maria Florencia
Praditsuktavorn, Pannee
Fernando, Tharu M.
Kwiatkowski, Nicholas
Marullo, Rosella
Calvo Vidal, M. Nieves
Phillip, Jude
Pera, Benet
Yang, Shao Ning
Takpradit, Kaipol
Roman, Lidia
Gaudiano, Marcello
Crescenzo, Ramona
Ruan, Jia
Inghirami, Giorgio
Zhang, Tinghu
Cremaschi, Graciela Alicia
Gray, Nathanael S.
Cerchietti, Leandro
author_role author
author2 Praditsuktavorn, Pannee
Fernando, Tharu M.
Kwiatkowski, Nicholas
Marullo, Rosella
Calvo Vidal, M. Nieves
Phillip, Jude
Pera, Benet
Yang, Shao Ning
Takpradit, Kaipol
Roman, Lidia
Gaudiano, Marcello
Crescenzo, Ramona
Ruan, Jia
Inghirami, Giorgio
Zhang, Tinghu
Cremaschi, Graciela Alicia
Gray, Nathanael S.
Cerchietti, Leandro
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Cdk7
Bcl2
T Cell Lymphoma
topic Cdk7
Bcl2
T Cell Lymphoma
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Peripheral T-cell lymphomas (PTCL) are aggressive diseases with poor response to chemotherapy and dismal survival. Identification of effective strategies to target PTCL biology represents an urgent need. Here we report that PTCL are sensitive to transcription-targeting drugs, and, in particular, to THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7). The STAT-signalling pathway is highly vulnerable to THZ1 even in PTCL cells that carry the activating STAT3 mutation Y640F. In mutant cells, CDK7 inhibition decreases STAT3 chromatin binding and expression of highly transcribed target genes like MYC, PIM1, MCL1, CD30, IL2RA, CDC25A and IL4R. In surviving cells, THZ1 decreases the expression of STAT-regulated anti-apoptotic BH3 family members MCL1 and BCL-XL sensitizing PTCL cells to BH3 mimetic drugs. Accordingly, the combination of THZ1 and the BH3 mimetic obatoclax improves lymphoma growth control in a primary PTCL ex vivo culture and in two STAT3-mutant PTCL xenografts, delineating a potential targeted agent-based therapeutic option for these patients.
Fil: Cayrol, Maria Florencia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina. Cornell University; Estados Unidos
Fil: Praditsuktavorn, Pannee. Cornell University; Estados Unidos
Fil: Fernando, Tharu M.. Cornell University; Estados Unidos
Fil: Kwiatkowski, Nicholas. Harvard Medical School; Estados Unidos
Fil: Marullo, Rosella. Cornell University; Estados Unidos
Fil: Calvo Vidal, M. Nieves. Cornell University; Estados Unidos
Fil: Phillip, Jude. Cornell University; Estados Unidos
Fil: Pera, Benet. Cornell University; Estados Unidos
Fil: Yang, Shao Ning. Cornell University; Estados Unidos
Fil: Takpradit, Kaipol. Cornell University; Estados Unidos
Fil: Roman, Lidia. Cornell University; Estados Unidos
Fil: Gaudiano, Marcello. Cornell University; Estados Unidos
Fil: Crescenzo, Ramona. Cornell University; Estados Unidos
Fil: Ruan, Jia. Cornell University; Estados Unidos
Fil: Inghirami, Giorgio. Cornell University; Estados Unidos
Fil: Zhang, Tinghu. Harvard Medical School; Estados Unidos
Fil: Cremaschi, Graciela Alicia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Gray, Nathanael S.. Harvard Medical School; Estados Unidos
Fil: Cerchietti, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Cornell University; Estados Unidos
description Peripheral T-cell lymphomas (PTCL) are aggressive diseases with poor response to chemotherapy and dismal survival. Identification of effective strategies to target PTCL biology represents an urgent need. Here we report that PTCL are sensitive to transcription-targeting drugs, and, in particular, to THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7). The STAT-signalling pathway is highly vulnerable to THZ1 even in PTCL cells that carry the activating STAT3 mutation Y640F. In mutant cells, CDK7 inhibition decreases STAT3 chromatin binding and expression of highly transcribed target genes like MYC, PIM1, MCL1, CD30, IL2RA, CDC25A and IL4R. In surviving cells, THZ1 decreases the expression of STAT-regulated anti-apoptotic BH3 family members MCL1 and BCL-XL sensitizing PTCL cells to BH3 mimetic drugs. Accordingly, the combination of THZ1 and the BH3 mimetic obatoclax improves lymphoma growth control in a primary PTCL ex vivo culture and in two STAT3-mutant PTCL xenografts, delineating a potential targeted agent-based therapeutic option for these patients.
publishDate 2017
dc.date.none.fl_str_mv 2017-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/55957
Cayrol, Maria Florencia; Praditsuktavorn, Pannee; Fernando, Tharu M.; Kwiatkowski, Nicholas; Marullo, Rosella; et al.; THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors; Nature; Nature Communications; 8; 1-2017; 1-11
2041-1723
CONICET Digital
CONICET
url http://hdl.handle.net/11336/55957
identifier_str_mv Cayrol, Maria Florencia; Praditsuktavorn, Pannee; Fernando, Tharu M.; Kwiatkowski, Nicholas; Marullo, Rosella; et al.; THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors; Nature; Nature Communications; 8; 1-2017; 1-11
2041-1723
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1038/ncomms14290
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/ncomms14290
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature
publisher.none.fl_str_mv Nature
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.48226

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