Diagenode

Transcriptional programming drives Ibrutinib-resistance evolution in mantlecell lymphoma.


Zhao, Xiaohong et al.

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.

Tags
Antibody

Share this article

Published
March, 2021

Source

Products used in this publication

  • ChIP-seq Grade
    C15100055-100
    Pol II Antibody
  • some alt
    C30010010-300
    1.5 ml Bioruptor® Plus TPX microtubes
  • some alt
    C30010010-50
    1.5 ml Bioruptor® Plus TPX microtubes
  • Bioruptor Pico
    B01080010
    Bioruptor® Pico sonication device

Events

  • Virtual ChIP workshop - January 18-19, 2022 or January 25-26, 2022
    Diagenode
    Jan 18-Jan 26, 2022
  • Virtual DNA Methylation - January 18-19, 2022 or January 25-26, 2022
    Diagenode
    Jan 18-Jan 26, 2022
  • Lausanne Genomics Days 2022
    Lausanne, Switzerland
    Feb 14-Feb 15, 2022
 See all events

News

 See all news


The European Regional Development Fund and Wallonia are investing in your future.

Extension of industrial buildings and new laboratories.


       Site map   |   Contact us   |   Conditions of sales   |   Conditions of purchase   |   Privacy policy   |   Diagenode Diagnostics