Cyclin-dependent kinase-9 is a therapeutic target in MYC-expressing diffuse large B-cell lymphoma

Taylor Hashiguchi, Nur Bruss, Scott Best, Vi Lam, Olga Danilova, Cody J. Paiva, Joelle Wolf, Erin Gilbert, Craig Y. Okada, Prabhjot Kaur, Lisa Drew, Justin Cidado, Peter Hurlin, Alexey V. Danilov

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Deregulation of the MYC transcription factor is a key driver in lymphomagenesis. MYC induces global changes in gene expression that contribute to cell growth, proliferation, and oncogenesis by stimulating the activity of RNA polymerases. A key feature in its ability to stimulate RNA Pol II activity is recruitment of pTEFb, an elongation factor whose catalytic core comprises CDK9/cyclin T complexes. Hence, MYC expression and function may be susceptible to CDK9 inhibition. We conducted a pre-clinical assessment of AZ5576, a selective CDK9 inhibitor, in diffuse large B-cell lymphoma (DLBCL). The in vitro and in vivo effects of AZ5576 on apoptosis, cell cycle, Mcl-1, and MYC expression were assessed by flow cytometry, immunoblotting, qPCR and RNA-Seq. We demonstrate that, in addition to depleting Mcl-1, targeting CDK9 disrupts MYC oncogenic function. Treatment with AZ5576 inhibited growth of DLBCL cell lines in vitro and in vivo, independent of cell-of-origin. CDK9 inhibition downregulated Mcl-1 and MYC mRNA transcript and protein in a dose-dependent manner. MYC-expressing cell lines demonstrated enhanced susceptibility to AZ5576. CDK9 inhibition promoted turnover of MYC protein, and decreased MYC phosphorylation at the stabilizing Ser62 residue and downregulated MYC transcriptional targets in DLBCL cells, a finding confirmed in a functional reporter assay, suggesting that CDK9 may govern MYC protein turnover, thus regulating its expression through multiple mechanisms. Our data suggest that targeting CDK9 is poised to disrupt MYC oncogenic activity in DLBCL and provide rationale for clinical development of selective CDK9 inhibitors.

Original languageEnglish (US)
Pages (from-to)1520-1532
Number of pages13
JournalMolecular cancer therapeutics
Volume18
Issue number9
DOIs
StatePublished - Jan 1 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Hashiguchi, T., Bruss, N., Best, S., Lam, V., Danilova, O., Paiva, C. J., Wolf, J., Gilbert, E., Okada, C. Y., Kaur, P., Drew, L., Cidado, J., Hurlin, P., & Danilov, A. V. (2019). Cyclin-dependent kinase-9 is a therapeutic target in MYC-expressing diffuse large B-cell lymphoma. Molecular cancer therapeutics, 18(9), 1520-1532. https://doi.org/10.1158/1535-7163.MCT-18-1023