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RNA-seq analysis evaluating effects of Cdk7 inhibitor THZ1 on responses of mouse hearts to transverse aortic artery constriction (TAC)

ABSTRACT: RNA-seq analysis evaluating effects of Cdk7 inhibitor THZ1 on responses of mouse hearts to TAC

ORGANISM(S): Mus musculus

PROVIDER: GSE151254 | GEO | 2022/04/25

REPOSITORIES: GEO

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RNA-seq analysis evaluating effects of Cdk7 inhibitor THZ1 on responses of mouse hearts to transverse aortic artery constriction (TAC)

Project description:RNA-seq analysis evaluating effects of Cdk7 inhibitor THZ1 on responses of mouse hearts to transverse aortic artery constriction (TAC)

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CDK7 inhibitor THZ1 induces the cell apoptosis of B-cell acute lymphocytic leukemia by perturbing cellular metabolism

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

Project 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-signaling 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.

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Expression data from mouse heart post transverse aortic constriction (TAC) -surgery 2 weeks

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