Transcriptional programming drives Ibrutinib-resistance evolution in mantle cell lymphoma

Xiaohong Zhao, Michelle Y. Wang, Huijuan Jiang, Tint Lwin, Paul M. Park, Jing Gao, Mark B. Meads, Yuan Ren, Tao Li, Jiao Sun, Naima Ahmed Fahmi, Satishkumar Singh, Lalit Sehgal, Xuefeng Wang, Ariosto S. Silva, Eduardo M. Sotomayor, Kenneth H. Shain, John L. Cleveland, Michael Wang, Wei ZhangJun Qi, Bijal D. Shah, Jianguo Tao

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Ibrutinib, a bruton's tyrosine kinase (BTK) inhibitor, provokes robust clinical responses in aggressive mantle cell lymphoma (MCL), yet many patients relapse with lethal Ibrutinib-resistant (IR) disease. Here, using genomic, chemical proteomic, and drug screen profiling, we report that enhancer remodeling-mediated transcriptional activation and adaptive signaling changes drive the aggressive phenotypes of IR. Accordingly, IR MCL cells are vulnerable to inhibitors of the transcriptional machinery and especially so to inhibitors of cyclin-dependent kinase 9 (CDK9), the catalytic subunit of the positive transcription elongation factor b (P-TEFb) of RNA polymerase II (RNAPII). Further, CDK9 inhibition disables reprogrammed signaling circuits and prevents the emergence of IR in MCL. Finally, and importantly, we find that a robust and facile ex vivo image-based functional drug screening platform can predict clinical therapeutic responses of IR MCL and identify vulnerabilities that can be targeted to disable the evolution of IR.

Original languageEnglish (US)
Article number108870
JournalCell Reports
Volume34
Issue number11
DOIs
StatePublished - Mar 16 2021

Keywords

  • BRD4
  • CDK9
  • Ibrutinib
  • combination therapy
  • enhancer
  • kinome
  • mantle cell lymphoma
  • resistance
  • transcriptome

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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