Cummin TE, et al. - In view of the observed worse survival in correlation to double-hit lymphoma and double-expressor diffuse large B cell lymphoma (DLBCL), both characterized by dysregulation of MYC and BCL-2, following treatment with current standard of care (R-CHOP) and surprisingly, limited activity of venetoclax, a BH3-mimetic that potently inhibits BCL-2, in this disease, researchers investigated the expression and potential prognostic relevance of all anti-apoptotic BCL-2 family members, not just BCL-2, in DLBCL. In addition, they examined how these might be overcome with new therapeutic approaches comprising a novel BET inhibitor (BETi), PLX2853, and its combination with the BH3-mimetics, venetoclax (BCL-2) and WEHI-539 (BCL-xL). Using the Whole Genome-DASL array from 928 patients from the REMoDL-B trial, DLBCL subtypes displayed differential mRNA expression patterns of anti-apoptotic BCL-2 family members. Potential mechanisms of cell death following exposure to BETi and BH3-mimetics were determined using E-myc lymphoma cell lines (LCLs) and DLBCL cell lines (CL) (4 GCB, 3 ABC). As per findings, treatment resistance in DLBCL is related to high BCL-xL expression. Resistance to BETi is also related to high expression of anti-apoptotic BCL-2 family members. However, using specific BH3-mimetics targeting the relevant pro-survival BCL-2 member, involving mitochondrial priming, could assist in overcoming this treatment resistance.