Seletive inhibition of CDK9 in DLBCL cell lines

Deregulation of the MYC transcription factor is a key driver in lymphomagenesis. MYC induces global changes in gene expression that contribute to cell growth, proliferation and oncogenesis by stimulating the activity of RNA polymerases. A key feature in its ability to stimulate RNA Pol II activity is recruitment of pTEFb, an elongation factor whose catalytic core comprises CDK9/cyclin T complexes. Hence, MYC expression and function may be susceptible to CDK9 inhibition. Non-specific inhibitors of multiple CDKs have shown promise in B-cell malignancies, where their pro-apoptotic effect has been attributed to a reduction in transcription and downmodulation of short lived pro-survival proteins (e.g., Mcl-1). However, they lack a defined mechanism of action. Here we selectively targeted CDK9 in a pre-clinical study in DLBCL. We employed gene expression profiling by RNA-Seq to determine which pathways were deregulated by AZ5576, a selective CDK9 inhibitor, in DLBCL cells. VAL cells and OCI-LY3 cells were treated with 0.3 µM AZ-5576 for 3 or 6 hours and comparisons in gene expression were made to vehicle-treated cells. Expression of 30,451 genes was detected in DLBCL cells. Using a cutoff of at least 2-fold change we identified between one and three thousand genes whose expression was significantly affected by AZ5576