CDK9 is a Dependency in GATA-3 driven and MCL-1 independent T-cell Lymphomas [ChIP-seq]

The transcription factor GATA-3 is a proto-oncogene in subsets of mature T cell lymphomas (TCL). CDK9 is a transcriptional regulator that, by phosphorylating paused RNA polymerase II (RNAPII), enables efficient transcriptional elongation. Therefore, we were motivated to examine the extent to which CDK9 is required for controlling transcription and expression of GATA-3 and its target genes. A pharmacologic strategy, using the selective CDK9 inhibitor AZD4573, was utilized to identify CDK9 dependent transcripts. Traveling ratios, defined as the ratio of RNAPII bound at promoter to RNAPII bound within the gene body, were determined by RNAPII ChIP-seq in cell treated with AZD4573 (or vehicle control). CDK9 dependent genes were defined as those with increased traveling ratio and decreased transcripts. MCL-1 dependency was determined in these cell lines by BH3 profiling. The extent to which CDK9 inhibition transcriptionally reprograms TCL was further examined in complementary ex vivo and in vivo studies using primary TCL specimens and GEM and PDX models