Journal Article

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

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

2021

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 13/109 / 13/31 / 14 / 14/19 / 14/32 / 14/34 / 38 / 38/22 / 38/39 / 59/5 / 59/57 / 631/67/1059/602 / 631/67/1990/291/1621/1915 / 82 / 82/1 / Adenine - administration & dosage / Adenine - analogs & derivatives / Animals / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Apoptosis / B-cell lymphoma / Bet protein / Biomarkers, Tumor - genetics / Biomarkers, Tumor - metabolism / Bridged Bicyclo Compounds, Heterocyclic - administration & dosage / c-Myc protein / Cancer Research / Care and treatment / Cell Proliferation / Cell Transformation, Neoplastic - drug effects / Cell Transformation, Neoplastic - metabolism / Cell Transformation, Neoplastic - pathology / Chromatin / Chronic lymphocytic leukemia / CRISPR / Critical Care Medicine / Development and progression / Enhancers / Gene expression / Gene Expression Regulation, Neoplastic / Gene mutations / Genetic aspects / Genetic transformation / Health aspects / Hematology / Humans / Inhibitor drugs / Inhibitors / Intensive / Interferon regulatory factor 4 / Internal Medicine / Lethality / Lymphocytes B / Lymphoma / Lymphoma, Large B-Cell, Diffuse - drug therapy / Lymphoma, Large B-Cell, Diffuse - metabolism / Lymphoma, Large B-Cell, Diffuse - pathology / Lymphomas / Medicine / Medicine & Public Health / Mice / mRNA / Myc protein / Oncology / Piperidines - administration & dosage / Proteins / Proteins - genetics / Proteins - metabolism / Proteolysis / Sensitivity / Sulfonamides - administration & dosage / Targeted cancer therapy / Therapy / Tumor Cells, Cultured / Xenograft Model Antitumor Assays / Xenografts / Xenotransplantation