Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Changes in gene expression induced by CDK9 inhibition alone and in combination with fludarabine

ABSTRACT: Using a transcriptomics approach we explored the mechanism(s) of synergy observed between CDKI-73 and fludarabine in primary CLL cells. The cytotoxic effects of CDKI-73 were associated with transcriptional inhibition of cdk9 target genes including MCL1 and XIAP. In contrast, fludarabine induced the transcription of these genes, an effect that was reversed by the combination of CDKI-73 and fludarabine. We used microarrays to explore the cytoxic synergy observed in primary CLL cells when we combined a novel CDK9 inhibitor with the purine nucleoside analogue fludarabine Primary CLL cells were inclubated with 0.1 Î¼M CDKI-73, 10 Î¼M fludarabine or the two drugs in combination for 4h.

ORGANISM(S): Homo sapiens

SUBMITTER: Chris Pepper

PROVIDER: E-GEOD-48258 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

A novel Cdk9 inhibitor preferentially targets tumor cells and synergizes with fludarabine.

Walsby Elisabeth E Pratt Guy G Shao Hao H Abbas Abdullah Y AY Fischer Peter M PM Bradshaw Tracey D TD Brennan Paul P Fegan Chris C Wang Shudong S Pepper Chris C

Oncotarget 20140101 2

Cdk9 is a key elongation factor for RNA transcription and functions by phosphorylating the C-terminal domain of RNA polymerase II. Here we present direct evidence that cdk9 is important for cancer cell survival and describe the characterization of the potent cdk9 inhibitor CDKI-73 in primary human leukemia cells. CDKI-73 induced caspase-dependent apoptosis that was preceded by dephosphorylation of cdk9 and serine 2 of RNA polymerase II. CDKI-73 was more potent than the pan-cdk inhibitor flavopir ...[more]

PMID: 24495868

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Project description:Chronic lymphocytic leukemic B cells (CLL) reside in close contact with activated endothelial cells (EC) in infiltrated tissues. Here, we investigated the interactions between EC and CLL cells, highlighting molecular networks involved in this cellular crosstalk. We co-cultured purified CLL cells on HUVEC monolayer (HC) or in medium alone. We found that EC protected CLL from spontaneous apoptosis. A 2.2-fold increase in relative viability in IGHV mutated CLL and a 6.1-fold increase in IGHV unmutated CLL was detected in co-culture. Moreover, the endothelial cell layer decreased the in vitro sensitivity of CLL cells to Fludarabine-induced apoptosis. Physical contact with EC is essential for protection to apoptosis. The insertion of a microporous membrane or blocking adhesion with anti-CD106 and anti-CD18 antibodies determined the complete abrogation of apoptosis protection. On the other hand, a reduction of apoptosis was measured in CLL cells cultured with conditioned medium collected from HC, implying that survival is partially mediated by soluble factors. Overall 1944 genes were modulated in CLL by co-culture. The EC contact seem to determine on CLL a kind of microenvironmental-driven angiogenic switch, improve the secretion of cytokines regulating tissue elements such as stromal cells and macrophages and also increase anti-apoptotic molecules. Our study support the line of evidence indicating endothelial cells as a major player in the CLL-infiltrated microenvironments are able to create a vicious cycle of cooperation that strongly sustains leukemic cell survival, protects CLL from drug-induced apoptosis and widely modifies CLL phenotype. Large-scale gene expression profiling (GEP) was performed on total RNA extracted from purified CD19+ cells isolated from 9 individual CLL patients which were separated in 3 experimental subsets: (i) freshly isolated cells (CLL baseline), (ii) CLL cells cultured in medium alone for 48 hours (CLL only) and (iii) CLL cells co-cultured 48h on HUVEC layer (CLL HC).

Dataset Information

Changes in gene expression induced by CDK9 inhibition alone and in combination with fludarabine

Publications

A novel Cdk9 inhibitor preferentially targets tumor cells and synergizes with fludarabine.

Similar Datasets

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