BET proteolysis targeted chimera-based therapy of novel models of Richter Transformation-diffuse large B-cell lymphoma

Warren Fiskus, Christopher P. Mill, Dimuthu Perera, Christine Birdwell, Qing Deng, Haopeng Yang, Bernardo H. Lara, Nitin Jain, Jan Burger, Alessandra Ferrajoli, John A. Davis, Dyana T. Saenz, Wendy Jin, Cristian Coarfa, Craig M. Crews, Michael R. Green, Joseph D. Khoury, Kapil N. Bhalla

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Richter Transformation (RT) develops in CLL as an aggressive, therapy-resistant, diffuse large B cell lymphoma (RT-DLBCL), commonly clonally-related (CLR) to the concomitant CLL. Lack of available pre-clinical human models has hampered the development of novel therapies for RT-DLBCL. Here, we report the profiles of genetic alterations, chromatin accessibility and active enhancers, gene-expressions and anti-lymphoma drug-sensitivity of three newly established, patient-derived, xenograft (PDX) models of RT-DLBCLs, including CLR and clonally-unrelated (CLUR) to concomitant CLL. The CLR and CLUR RT-DLBCL cells display active enhancers, higher single-cell RNA-Seq-determined mRNA, and protein expressions of IRF4, TCF4, and BCL2, as well as increased sensitivity to BET protein inhibitors. CRISPR knockout of IRF4 attenuated c-Myc levels and increased sensitivity to a BET protein inhibitor. Co-treatment with BET inhibitor or BET-PROTAC and ibrutinib or venetoclax exerted synergistic in vitro lethality in the RT-DLBCL cells. Finally, as compared to each agent alone, combination therapy with BET-PROTAC and venetoclax significantly reduced lymphoma burden and improved survival of immune-depleted mice engrafted with CLR-RT-DLBCL. These findings highlight a novel, potentially effective therapy for RT-DLBCL.

Original languageEnglish (US)
Pages (from-to)2621-2634
Number of pages14
JournalLeukemia
Volume35
Issue number9
DOIs
StatePublished - Sep 2021
Externally publishedYes

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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