THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors
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 parti...
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| Formato: | Artículo |
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Springer Nature
2019
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| Acceso en línea: | https://repositorio.uca.edu.ar/handle/123456789/8653 |
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I33-R139-123456789-86532024-03-07T11:59:03Z THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors 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 INMUNOLOGIA MEDICINA BASICA PROTEINAS SANGRE 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. 2019-08-28T23:30:21Z 2019-08-28T23:30:21Z 2017 Artículo 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 2041-1723 https://repositorio.uca.edu.ar/handle/123456789/8653 10.1038/ncomms14290 28134252 eng Acceso Abierto http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Springer Nature Nature Communications. 2017;8:14290 |
| institution |
Universidad Católica Argentina |
| institution_str |
I-33 |
| repository_str |
R-139 |
| collection |
Repositorio Institucional de la Universidad Católica Argentina (UCA) |
| language |
Inglés |
| topic |
INMUNOLOGIA MEDICINA BASICA PROTEINAS SANGRE |
| spellingShingle |
INMUNOLOGIA MEDICINA BASICA PROTEINAS SANGRE 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 THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors |
| topic_facet |
INMUNOLOGIA MEDICINA BASICA PROTEINAS SANGRE |
| description |
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. |
| format |
Artículo |
| author |
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_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_sort |
Cayrol, María Florencia |
| title |
THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors |
| 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 |
| publisher |
Springer Nature |
| publishDate |
2019 |
| url |
https://repositorio.uca.edu.ar/handle/123456789/8653 |
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