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

Autores
Cayrol, María 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 A.; Gray, Nathanael S.; Cerchietti, Leandro
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Fil: Caryrol, Florencia. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Caryrol, Florencia. Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Neuroinmunomodulación y Oncología Molecular; Argentina
Fil: Cayrol, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Praditsuktavorn, Pannee. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Fernando, Tharu M. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Kwiatkowski, Nicholas. Harvard Medical School. Department of Biological Chemistry and Molecular Pharmacology. Dana-Farber Cancer Institute. Department of Cancer Biology; Estados Unidos
Fil: Marullo, Rosella. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Calvo-Vidal, M. Nieves. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Phillip, Jude. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Pera, Benet. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Yang, Shao Ning. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Takpradit, Kaipol. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Roman, Lidia. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Gaudiano, Marcello. Weill Cornell Medicine. Department of Pathology and Laboratory Medicine; Estados Unidos
Fil: Crescenzo, Ramona. Weill Cornell Medicine. Department of Pathology and Laboratory Medicine; Estados Unidos
Fil: Ruan, Jia. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Inghirami, Giorgio. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Zhang, Tinghu. Harvard Medical School. Department of Biological Chemistry and Molecular Pharmacology. Dana-Farber Cancer Institute. Department of Cancer Biology; Estados Unidos
Fil: Cremaschi, Graciela A. Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Neuroinmunomodulación y Oncología Molecular; Argentina
Fil: Cremaschi, Graciela A. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Gray, Nathanael S. Harvard Medical School. Department of Biological Chemistry and Molecular Pharmacology. Dana-Farber Cancer Institute. Department of Cancer Biology; Estados Unidos
Fil: Cerchietti, Leandro. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Abstract: 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.
Fuente
Nature Communications. 2017;8:14290
Materia
INMUNOLOGIA
MEDICINA BASICA
PROTEINAS
SANGRE
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/4.0/
Repositorio
Repositorio Institucional (UCA)
Institución
Pontificia Universidad Católica Argentina
OAI Identificador
oai:ucacris:123456789/8653
Acceder
id RIUCA_55cae7b2f9aeaf5a9e23a468a1ee944e
oai_identifier_str oai:ucacris:123456789/8653
network_acronym_str RIUCA
repository_id_str 2585
network_name_str Repositorio Institucional (UCA)
spelling THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitorsCayrol, María FlorenciaPraditsuktavorn, PanneeFernando, Tharu M.Kwiatkowski, NicholasMarullo, RosellaCalvo Vidal, M. NievesPhillip, JudePera, BenetYang, Shao NingTakpradit, KaipolRoman, LidiaGaudiano, MarcelloCrescenzo, RamonaRuan, JiaInghirami, GiorgioZhang, TinghuCremaschi, Graciela A.Gray, Nathanael S.Cerchietti, LeandroINMUNOLOGIAMEDICINA BASICAPROTEINASSANGREFil: Caryrol, Florencia. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados UnidosFil: Caryrol, Florencia. Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Neuroinmunomodulación y Oncología Molecular; ArgentinaFil: Cayrol, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Praditsuktavorn, Pannee. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados UnidosFil: Fernando, Tharu M. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados UnidosFil: Kwiatkowski, Nicholas. Harvard Medical School. Department of Biological Chemistry and Molecular Pharmacology. Dana-Farber Cancer Institute. Department of Cancer Biology; Estados UnidosFil: Marullo, Rosella. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados UnidosFil: Calvo-Vidal, M. Nieves. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados UnidosFil: Phillip, Jude. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados UnidosFil: Pera, Benet. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados UnidosFil: Yang, Shao Ning. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados UnidosFil: Takpradit, Kaipol. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados UnidosFil: Roman, Lidia. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados UnidosFil: Gaudiano, Marcello. Weill Cornell Medicine. Department of Pathology and Laboratory Medicine; Estados UnidosFil: Crescenzo, Ramona. Weill Cornell Medicine. Department of Pathology and Laboratory Medicine; Estados UnidosFil: Ruan, Jia. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados UnidosFil: Inghirami, Giorgio. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados UnidosFil: Zhang, Tinghu. Harvard Medical School. Department of Biological Chemistry and Molecular Pharmacology. Dana-Farber Cancer Institute. Department of Cancer Biology; Estados UnidosFil: Cremaschi, Graciela A. Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Neuroinmunomodulación y Oncología Molecular; ArgentinaFil: Cremaschi, Graciela A. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gray, Nathanael S. Harvard Medical School. Department of Biological Chemistry and Molecular Pharmacology. Dana-Farber Cancer Institute. Department of Cancer Biology; Estados UnidosFil: Cerchietti, Leandro. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados UnidosAbstract: 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.Springer Nature2017info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfhttps://repositorio.uca.edu.ar/handle/123456789/86532041-172310.1038/ncomms1429028134252Cayrol F, Praditsuktavorn P, Fernando TM, et al. THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors [en línea]. Nature Communications. 2017;8:14290. doi: 10.1038/ncomms14290 Disponible en: https://repositorio.uca.edu.ar/handle/123456789/8653Nature Communications. 2017;8:14290reponame:Repositorio Institucional (UCA)instname:Pontificia Universidad Católica Argentinaenginfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/4.0/2025-07-03T10:56:52Zoai:ucacris:123456789/8653instacron:UCAInstitucionalhttps://repositorio.uca.edu.ar/Universidad privadaNo correspondehttps://repositorio.uca.edu.ar/oaiclaudia_fernandez@uca.edu.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:25852025-07-03 10:56:52.573Repositorio Institucional (UCA) - Pontificia Universidad Católica Argentinafalse
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, María Florencia
INMUNOLOGIA
MEDICINA BASICA
PROTEINAS
SANGRE
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, María 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 A.
Gray, Nathanael S.
Cerchietti, Leandro
author Cayrol, María Florencia
author_facet Cayrol, María 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 A.
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 A.
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 INMUNOLOGIA
MEDICINA BASICA
PROTEINAS
SANGRE
topic INMUNOLOGIA
MEDICINA BASICA
PROTEINAS
SANGRE
dc.description.none.fl_txt_mv Fil: Caryrol, Florencia. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Caryrol, Florencia. Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Neuroinmunomodulación y Oncología Molecular; Argentina
Fil: Cayrol, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Praditsuktavorn, Pannee. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Fernando, Tharu M. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Kwiatkowski, Nicholas. Harvard Medical School. Department of Biological Chemistry and Molecular Pharmacology. Dana-Farber Cancer Institute. Department of Cancer Biology; Estados Unidos
Fil: Marullo, Rosella. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Calvo-Vidal, M. Nieves. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Phillip, Jude. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Pera, Benet. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Yang, Shao Ning. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Takpradit, Kaipol. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Roman, Lidia. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Gaudiano, Marcello. Weill Cornell Medicine. Department of Pathology and Laboratory Medicine; Estados Unidos
Fil: Crescenzo, Ramona. Weill Cornell Medicine. Department of Pathology and Laboratory Medicine; Estados Unidos
Fil: Ruan, Jia. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Inghirami, Giorgio. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Fil: Zhang, Tinghu. Harvard Medical School. Department of Biological Chemistry and Molecular Pharmacology. Dana-Farber Cancer Institute. Department of Cancer Biology; Estados Unidos
Fil: Cremaschi, Graciela A. Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Neuroinmunomodulación y Oncología Molecular; Argentina
Fil: Cremaschi, Graciela A. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Gray, Nathanael S. Harvard Medical School. Department of Biological Chemistry and Molecular Pharmacology. Dana-Farber Cancer Institute. Department of Cancer Biology; Estados Unidos
Fil: Cerchietti, Leandro. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
Abstract: 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.
description Fil: Caryrol, Florencia. Weill Cornell Medicine. Hematology and Oncology Division. Department of Medicine; Estados Unidos
publishDate 2017
dc.date.none.fl_str_mv 2017
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 https://repositorio.uca.edu.ar/handle/123456789/8653
2041-1723
10.1038/ncomms14290
28134252
Cayrol F, Praditsuktavorn P, Fernando TM, et al. THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors [en línea]. Nature Communications. 2017;8:14290. doi: 10.1038/ncomms14290 Disponible en: https://repositorio.uca.edu.ar/handle/123456789/8653
url https://repositorio.uca.edu.ar/handle/123456789/8653
identifier_str_mv 2041-1723
10.1038/ncomms14290
28134252
Cayrol F, Praditsuktavorn P, Fernando TM, et al. THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors [en línea]. Nature Communications. 2017;8:14290. doi: 10.1038/ncomms14290 Disponible en: https://repositorio.uca.edu.ar/handle/123456789/8653
dc.language.none.fl_str_mv eng
language eng
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/4.0/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/4.0/
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv Nature Communications. 2017;8:14290
reponame:Repositorio Institucional (UCA)
instname:Pontificia Universidad Católica Argentina
reponame_str Repositorio Institucional (UCA)
collection Repositorio Institucional (UCA)
instname_str Pontificia Universidad Católica Argentina
repository.name.fl_str_mv Repositorio Institucional (UCA) - Pontificia Universidad Católica Argentina
repository.mail.fl_str_mv claudia_fernandez@uca.edu.ar
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score 13.216834

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