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| Status |
Public on Nov 02, 2020 |
| Title |
Ant-leukemic effect of CDK9 inhibition in T-cell prolymphocytic leukemia (microRNA) |
| Platform organism |
synthetic construct |
| Sample organism |
Homo sapiens |
| Experiment type |
Non-coding RNA profiling by array
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| Summary |
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.
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| Overall design |
After tumor cell enrichment for T-PLL cells we performed miRNA profiling with GeneChip miRNA 3.0 arrays (Affymetrix, Santa Clara, CA) and Microarray based gene expression profiling (GEP). GEP was performed using high-densitiy oligonucleotide arrays (Clariom S, Affymetrix, Santa Clara, CA, USA).
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| Contributor(s) |
Johansson P, Dierichs L, Klein-Hitpass L, Bergmann AK, Möllmann M, Menninger S, Habenberger P, Klebl B, Siveke JT, Dührsen U, Choidas A, Dürig J |
| Citation(s) |
33117517 |
| Submission date |
Aug 05, 2020 |
| Last update date |
Nov 02, 2020 |
| Contact name |
Rene Scholtysik |
| E-mail(s) |
rene.scholtysik@uni-due.de
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| Organization name |
University Hospital Essen
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| Department |
IFZ
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| Street address |
Virchowstrasse 173
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| City |
Essen |
| ZIP/Postal code |
45127 |
| Country |
Germany |
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| Platforms (1) |
| GPL16384 |
[miRNA-3] Affymetrix Multispecies miRNA-3 Array |
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| Samples (15)
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| Relations |
| BioProject |
PRJNA655477 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE155746_RAW.tar |
38.7 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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