Please use this identifier to cite or link to this item: https://repositorio.uca.edu.ar/handle/123456789/8653
Título : THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors
Autor : 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 
Palabras clave : INMUNOLOGIAMEDICINA BASICAPROTEINASSANGRE
Fecha de publicación : 2017
Editorial : Springer Nature
Cita : 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
Resumen : 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.
URI : https://repositorio.uca.edu.ar/handle/123456789/8653
ISSN : 2041-1723
Disciplina: MEDICINA
DOI: 10.1038/ncomms14290
Derechos: Acceso Abierto
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