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

• DOI: 10.1038/s41375-021-01181-w
• Publication Date: 2021-03-02T08:03:02Z
• Authors: 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
• Keywords: Venetoclax

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 development novel therapies for RT-DLBCL. Here, we report profiles genetic alterations, chromatin accessibility and active enhancers, gene-expressions anti-lymphoma drug-sensitivity three newly established, patient-derived, xenograft (PDX) RT-DLBCLs, including CLR clonally-unrelated (CLUR) The CLUR RT-DLBCL cells display higher single-cell RNA-Seq-determined mRNA, protein expressions IRF4, TCF4, BCL2, well increased sensitivity BET inhibitors. CRISPR knockout IRF4 attenuated c-Myc levels a inhibitor. Co-treatment with inhibitor or BET-PROTAC ibrutinib venetoclax exerted synergistic vitro lethality cells. Finally, compared each agent alone, combination therapy significantly reduced burden improved survival immune-depleted mice engrafted CLR-RT-DLBCL. These findings highlight novel, potentially effective