CDK9 is a dependency in GATA-3 driven and MCL-1 independent T-cell Lymphomas

The transcription factor GATA-binding protein 3 (GATA-3) regulates oncogenic transcriptional programs across diverse T-cell lymphomas, including subsets of both peripheral and primary cutaneous T-cell lymphomas. These GATA-3 dependent transcriptional programs, in collaboration with the genetic landscape, promote cell growth and survival, and confer resistance to conventional chemotherapeutic agents. We observed that transcriptional cyclin dependent kinase 9 (CDK9) activation regulates diverse oncogenic transcriptional programs in these aggressive T-cell lymphomas and is thus a novel therapeutic vulnerability. Using complementary and orthogonal approaches, we identified multiple independent mechanisms by which CDK9 promotes T-cell lymphomagenesis, including a mechanism by which GATA-3 promotes CDK9 activation at GATA-3 dependent loci. We also identify novel mechanisms by which GATA-3 and CDK9 regulate rRNA transcription and processing, respectively, collaboratively promoting ribosome biogenesis. Therefore, CDK9 is a therapeutic vulnerability across genetically and transcriptionally diverse T-cell lymphomas, including those for which GATA-3 is oncogenic.