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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月27日

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  • Chenguang Wang,
  • Suhaib Abdelrahman,
  • Xiangrong Geng,
  • Alyssa Burgess,
  • Ying S. Hu,
  • Mohd Ahmar Rauf,
  • Nermin Kady,
  • Yao Fu,
  • Tara A. Reilly,
  • Ira P. Maine,
  • Phillip Boonstra,
  • Kirill Sabitov,
  • Carlos Murga-Zamalloa,
  • Ryan A. Wilcox

摘要

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.