Ant-leukemic effect of CDK9 inhibition in T-cell prolymphocytic leukemia (microRNA)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA655477 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Ant-leukemic effect of CDK9 inhibition in T-cell prolymphocytic leukemia (mRNA)
| PRJNA655478 | ENA
Project description:We investigated the pharmacological effects of the novel highly specific cyclin-dependent kinase 9 (CDK9) inhibitor LDC526 and its clinically used derivate atuveciclib employing primary T-PLL cells in an ex vivo drug sensitivity testing platform. All T-PLL samples were sensitive to CDK9 inhibition at submicromolar concentrations while conventional cytotoxic drugs were found to be largely ineffective. At the cellular level LDC526 inhibited the phosphorylation at serine 2 of the RNA polymerase II C-terminal domain resulting in decreased de novo RNA transcription. LDC526 induced apoptotic leukemic cell death through down-regulating MYC and MCL1 both at the mRNA and protein level. Microarray based transcriptomic profiling revealed that genes down-modulated in response to CDK9 inhibition were enriched for MYC and JAK-STAT targets. By contrast, CDK9 inhibition increased the expression of the tumor suppressor FBXW7 which may contribute to decreased MYC and MCL1 protein levels. The combination of atuvecliclib and the BCL2 inhibitor venetoclax exhibited synergistic anti-leukemic activity, providing the rationale for a novel targeted-agent based treatment of T-PLL.
2020-11-02 | GSE155746 | GEO
Project description:We investigated the pharmacological effects of the novel highly specific cyclin-dependent kinase 9 (CDK9) inhibitor LDC526 and its clinically used derivate atuveciclib employing primary T-PLL cells in an ex vivo drug sensitivity testing platform. All T-PLL samples were sensitive to CDK9 inhibition at submicromolar concentrations while conventional cytotoxic drugs were found to be largely ineffective. At the cellular level LDC526 inhibited the phosphorylation at serine 2 of the RNA polymerase II C-terminal domain resulting in decreased de novo RNA transcription. LDC526 induced apoptotic leukemic cell death through down-regulating MYC and MCL1 both at the mRNA and protein level. Microarray based transcriptomic profiling revealed that genes down-modulated in response to CDK9 inhibition were enriched for MYC and JAK-STAT targets. By contrast, CDK9 inhibition increased the expression of the tumor suppressor FBXW7 which may contribute to decreased MYC and MCL1 protein levels. The combination of atuvecliclib and the BCL2 inhibitor venetoclax exhibited synergistic anti-leukemic activity, providing the rationale for a novel targeted-agent based treatment of T-PLL.
2020-11-02 | GSE155747 | GEO
Project description:T-cell prolymphocytic leukemia (T-PLL) is an aggressive malignancy characterized by chemotherapy resistance and a median survival of less than 2 years. Here, we investigated the pharmacological effects of the novel highly specific cyclin-dependent kinase 9 (CDK9) inhibitor LDC526 and its clinically used derivate atuveciclib employing primary T-PLL cells in an ex vivo drug sensitivity testing platform. Importantly, all T-PLL samples were sensitive to CDK9 inhibition at submicromolar concentrations, while conventional cytotoxic drugs were found to be largely ineffective. At the cellular level LDC526 inhibited the phosphorylation at serine 2 of the RNA polymerase II C-terminal domain resulting in decreased de novo RNA transcription. LDC526 induced apoptotic leukemic cell death through down-regulating MYC and MCL1 both at the mRNA and protein level. Microarray-based transcriptomic profiling revealed that genes down-modulated in response to CDK9 inhibition were enriched for MYC and JAK-STAT targets. By contrast, CDK9 inhibition increased the expression of the tumor suppressor FBXW7, which may contribute to decreased MYC and MCL1 protein levels. Finally, the combination of atuvecliclib and the BCL2 inhibitor venetoclax exhibited synergistic anti-leukemic activity, providing the rationale for a novel targeted-agent-based treatment of T-PLL.
| S-EPMC7570784 | biostudies-literature
Project description:In this study, we discovered that CDK9-mediated, RNAPII-driven transcription is functionally opposed by a protein phosphatase 2A (PP2A) complex that is recruited to transcription sites by the Integrator complex subunit INTS6. PP2A dynamically antagonises phosphorylation of key CDK9 substrates including DSIF and RNAPII-CTD. Loss of INTS6 results in resistance to tumor cell death mediated by CDK9 inhibition, decreased turnover of CDK9 phospho-substrates and amplification of acute cell growth and pro-inflammatory transcriptional responses. Pharmacological PP2A activation synergizes with CDK9 inhibition to kill both leukemic and solid tumor cells, providing therapeutic benefit in vivo. These data demonstrate that finely-tuned gene expression relies on the balance of kinase and phosphatase activity throughout the transcription cycle.
2022-08-12 | PXD025060 | Pride
Project description:T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. To characterize the gene expression profiles, 12 T-PLL MNC samples (>90% tumor cell content) were screened with Illumina gene expression arrays (Human HT‐12 v4 rev.2 Expression Beadchips).
2017-09-08 | E-MTAB-5916 | biostudies-arrayexpress
Project description:T-cell prolymphocytic leukemina (T-PLL) is an agressive lymphoma derived from mature T-cells, which is in most cases characterized by the presence of an inv(14)(q11q32) and a characteristic pattern of secondary chromosomal abberations. We used microarrays to compare the transcriptomes of eight immunomagnetically purified CD3+ normal donor derived peripheral blood cells with five highly purified inv(14)-positive T-PLL blood samples. Keywords: desease state analysis
2007-08-27 | GSE5788 | GEO
Project description:Epigenetic therapy overcame alemtuzumab resistance in patients with relapsed T-cell prolymphocytic leukemia and induced the expression of treatment related genes. Method: patient PBMCs from Ficoll, normal patient PBMCS enriched for CD3+/CD8+ or CD3+/CD8+/CD45RA+/CCR7- were extracted in Trizol. Conclusion: Gene expression profiles were changed by epigenetic therapy, likely activating treatment response genes silenced by carcinogenesis.
2015-07-08 | GSE67368 | GEO
Project description:CDK9 is the kinase subunit of P-TEFb that enables RNA polymerase (Pol) II to transit from promoter-proximal pausing to productive elongation. Although considerable interest exists in CDK9 as a therapeutic target, little progress has been made due to the lack of highly selective inhibitors. Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing. While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment. Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9’s activity and resistance to inhibition. Because the i-CDK9-induced MYC expression and binding to P-TEFb compensate for P-TEFb’s loss of activity, only the simultaneous inhibition of CDK9 and MYC can efficiently induce growth arrest and apoptosis of cancer cells, suggesting the potential of a combinatorial treatment strategy. We used microarrays to examine the global impact on gene expression by imhibiting CDK9 at different time durations. HeLa cell lines treated with CDK9 inhibitor at different time points
2015-06-17 | E-GEOD-60952 | biostudies-arrayexpress
Project description:Epigenetic therapy overcame alemtuzumab resistance in patients with relapsed T-cell prolymphocytic leukemia and induced the expression of treatment related genes. Method: patient PBMCs from Ficoll, normal patient PBMCS enriched for CD3+/CD8+ or CD3+/CD8+/CD45RA+/CCR7- were extracted in Trizol. Conclusion: Gene expression profiles were changed by epigenetic therapy, likely activating treatment response genes silenced by carcinogenesis. Total RNA from patient Peripheral Blood Mononuclear Cells (PBMC) or from normal negatively enriched CD3+/CD8+/CCR7-/CD45RA+(CD45RO-) blood
2015-07-08 | E-GEOD-67368 | biostudies-arrayexpress