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

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE296506 | GEO | 2025/11/28

REPOSITORIES: GEO

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

Project description: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

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CDK9 inhibition with AZD4573 in DLBCL

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AZD4573 is a highly selective CDK9 inhibitor that suppresses Mcl-1 and induces apoptosis in hematological cancer cells

Project description:Phosphorylation of RNA polymerase II by cyclin-dependent kinase 9 (CDK9) is crucial for transcriptional regulation, and acute inhibition of CDK9 results in the rapid downregulation of genes with short-lived transcripts and labile proteins. Multiple non-selective CDK9 inhibitors have progressed clinically but were limited by a narrow therapeutic window. This work describes a novel, potent, and highly selective CDK9 inhibitor, AZD4573. Using integrated transcriptomic and proteomic analyses, loss-of-function pathway interrogation, and pharmacological comparisons, Mcl-1 depletion was identified as a major mechanism through which AZD4573 induces cell death in tumor cells. AZD4573 suppresses Mcl-1 in a dose- and time-dependent manner that causes caspase-3 cleavage in sensitive cancer cells, most notably in hematological malignancies. This pharmacodynamic response is observed in vivo as well, which leads to regressions in both subcutaneous tumor xenografts and disseminated models at tolerated doses as monotherapy or in combination with venetoclax. Fully understanding the mechanism, exposure, and anti-tumor activity of AZD4573 also informed the development of a robust PK/PD/efficacy model that helped select and predict the starting and efficacious dose range in man. Accordingly, AZD4573 is currently being evaluated in a phase I clinical trial for patients with hematological malignancies (clinicaltrials.gov identifier: NCT03263637).

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RNA-seq data corresponding to: AZD4573 is a highly selective CDK9 inhibitor that suppresses Mcl-1 and induces apoptosis in hematological cancer cells

Project description:A time-course RNA-seq experiment testing the effect of drug treatment using selective CDK9 inhibitor AZD4573. The experiment was done using a resistant cell-line to AZD4573: the MCF7 breast cancer cell-line.

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CDK9 inhibition with AZD4573 in DLBCL

Project description:We report the effects of CDK9 inhibition (AZD4573) on the epigenetic landscape in Diffuse Large B-cell Lymphoma (DLBCL). This study utilized the Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) to assess genome-wide chromatin accessibility in two DLBCL cell lines, OCI-LY3 and VAL, treated with AZD4573 (30 nM) at 0, 3, and 8 hours. We found that CDK9 inhibition led to gain and loss of accessible chromatin genome-wide, with enrichment of CTCF/BORIS motifs in decreased accesibility regions.

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CDK9 inhibition with AZD4573 in DLBCL

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CDK9 inhibition with AZD4573 in DLBCL

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The GATA-3 dependent transcriptome and tumor microenvironment are regulated by eIF4E and XPO1 in T-cell lymphomas

Project description:The transcription factor GATA-3 and the transcriptional program it regulates have emerged as oncogenic drivers across diverse T-cell lymphomas (TCL), many of which are resistant to conventional chemotherapeutic agents and characterized by recurrent losses of key tumor suppressor genes, including TP53 and PTEN, both of which are clients of the nuclear export protein XPO1. Here we demonstrated that XPO1 is highly expressed by malignant T cells expressing GATA-3 and by lymphoma-associated macrophages (LAM) within their tumor microenvironment (TME). Using complementary genetically engineered mouse (GEM) models, we demonstrated that TP53 and/or PTEN deficient TCL, and LAM within their TME, are sensitive to the selective XPO1 antagonist selinexor. In an effort to identify TP53 and PTEN independent mechanisms, we used complementary and orthogonal approaches to investigate the role of eIF4e and XPO1-dependent mRNA nuclear export in these TCL. We identified a novel role for eIF4E/XPO1 in exporting GATA-3 and GATA-3-dependent transcripts from the nucleus in TCL, and in the export of therapeutically relevant transcripts, including CSF-1R, from LAM. Therefore, XPO1 antagonism, by impairing oncogenic transcriptional programs in TCL and depleting LAM from their TME, is a novel approach to target two independent dependencies in a group of therapeutically challenging TCL.

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Unraveling the CDK9/PP2A/ERK network in transcriptional pause release and complement activation in KRAS-mutant cancers

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In vivo live imaging of RNA polymerase II transcription factories in primary cells

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