Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma [ATAC-Seq]

RichterTransformation (RT) develops in CLL as an aggressive, therapy resistant diffuse large B cell lymphoma (RT-DLBCL), commonly clonally related (CLR) to the antecedent CLL. Lack of available pre-clinical models has hampered development of novel therapies for RT-DLBCL. Here,we report the profiles of genetic alterations, active enhancers, gene-expressions and anti-lymphoma drug-sensitivity patterns of first-ever established, patient-derived xenograft models of RT-DLBCLs, including CLR and clonally unrelated (CLUR) to antecedent 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. This correlated with higher sensitivity to BET inhibitor and BET-PROTAC-based combinations with ibrutinib or venetoclax, including improved in vivo tumor burden and survival in the PDX model of CLR-RT-DLBCL. Overall design: Examination of chromtin accessibility by ATAC-Seq analysis in Diffuse Large B cell Lymphoma PDX cells