TY - JOUR TI - BET proteolysis targeted chimera-based therapy of novel models of Richter Transformation-diffuse large B-cell lymphoma AU - Fiskus, Warren AU - Mill, Christopher P. AU - Perera, Dimuthu AU - Birdwell, Christine AU - Deng, Qing AU - Yang, Haopeng AU - Lara, Bernardo H. AU - Jain, Nitin AU - Burger, Jan AU - Ferrajoli, Alessandra AU - Davis, John A. AU - Saenz, Dyana T. AU - Jin, Wendy AU - Coarfa, Cristian AU - Crews, Craig M. AU - Green, Michael R. AU - Khoury, Joseph D. AU - Bhalla, Kapil N. T2 - Leukemia AB - 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. DA - 2021/03/02/ PY - 2021 DO - 10.1038/s41375-021-01181-w DP - www.nature.com SP - 1 EP - 14 LA - en SN - 1476-5551 UR - https://www.nature.com/articles/s41375-021-01181-w Y2 - 2021/03/03/01:00:21 ER -