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

Sep 30, 2026

Uploaded by Theodore

CDK9 activation drives multiple oncogenic transcriptional programs in aggressive T-cell lymphomas regulated by the transcription factor GATA-3, representing a novel therapeutic vulnerability. Using complementary, orthogonal approaches, the study delineates independent mechanisms through which CDK9 promotes T-cell lymphomagenesis, including GATA-3-dependent control of CDK9 activation and coordinated regulation of rRNA transcription and processing. Together, these pathways enhance ribosome biogenesis and support survival. The results indicate CDK9 as a broadly relevant vulnerability across genetically and transcriptionally diverse T-cell lymphomas.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Introduction

Peripheral and primary cutaneous T-cell lymphomas

Transcriptional programs and treatment resistance

Therapeutic vulnerability of CDKs and CDK9

Blood Cancer [Journal](Journal www.nature.com/bcj)[ www.nature.com/bcj](Journal www.nature.com/bcj) ARTICLE OPEN CDK9 is a dependency in GATA-3 driven and MCL-1 independent T-cell Lymphomas Chenguang Wang 1,6 ✉, Suhaib Abdelrahman1,6, Xiangrong Geng 1,6, Alyssa Burgess2, Ying S. Hu2, Mohd Ahmar Rauf1, Nermin Ryan A. Kady1,3, Yao Fu1, Tara A. Reilly1, Ira P. Maine 1, Phillip Boonstra4, Kirill Sabitov 4, Carlos Murga-Zamalloa 5 and Wilcox 1 ✉ © The Author(s) 2025 | | 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. | | | | | Blood Cancer Journal (2026)16:9; [https://doi.org/10.1038/s41408-025-01427-1](https://doi.org/10.1038/s41408-025-01427-1) | | | | | | INTRODUCTION Peripheral T-cell lymphomas (PTCL) are derived from mature, post-thymic T cells, and while they account for ≈10% of nonHodgkin lymphomas (NHL), they increasingly account for a disproportionate number of lymphoma-related deaths, as the signiﬁcant therapeutic gains achieved for the more common B-cell NHL have not yet been realized for many PTCL subtypes, as currently available therapies are rarely curative and mechanisms of treatment resistance are poorly understood [1] . In fact, the most prevalent PTCL subtype worldwide is heterogeneous and remains “not otherwise speciﬁed” (PTCL, NOS), a subset of which, despite treatment with standard frontline anthracyclinebased chemotherapy, anticipate an overall survival that is not signiﬁcantly different from those undergoing hospice care alone [2] . Oncogenic transcriptional programs, the genetic landscape, and the tumor microenvironment (TME) collaboratively promote PTCL pathogenesis and treatment resistance [1, 3, 4] . For example, interactions between antigen-presenting cells within the TME and malignant T cells culminate in activation of antigen- and costimulatory-receptor dependent transcriptional programs [2, 5, 6] . Gain-of-function alterations in cell surface receptors or their downstream signaling intermediates stabilize these receptor-ligand interactions or further amplify liganddependent signaling, respectively [7–10] . Copy number alterations affecting oncogenes (including MYC) and tumor suppressors (including TP53 and PTEN) are recurrently observed and further promote the biomass production required for cell proliferation [11–13] . While the potential role of anti-apoptotic proteins in treatment resistance is incompletely understood, MCL-1 is highly expressed in the majority of PTCL [14], a subset of which are MCL-1 dependent [15] . Primary cutaneous T-cell lymphomas (CTCL), particularly those with large cell transformation (LCT), share transcriptional and genetic characteristics, and potential therapeutic vulnerabilities, with treatment refractory PTCL, NOS [2

FAQs

What role does GATA-3 play in T-cell lymphoma transcriptional programs?

GATA-3 regulates oncogenic transcriptional programs across diverse T-cell lymphomas, promoting growth and survival and contributing to resistance to conventional chemotherapy.

How is CDK9 described in this study?

CDK9 is identified as a dependency whose activation regulates multiple oncogenic transcriptional programs, making it a novel therapeutic vulnerability in aggressive T-cell lymphomas.

What coordinated mechanism links GATA-3 and CDK9 to ribosome biogenesis?

The study identifies mechanisms where GATA-3 and CDK9 regulate rRNA transcription and processing, collaboratively promoting ribosome biogenesis.

Sep 30, 2026

Uploaded by Theodore