biostudies-literatureVareli ANIAID NIH HHSMedical Research CouncilBlood Cancer UKU.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)620https://www.ebi.ac.uk/biostudies/studies/S-EPMC12357900biostudies-literatureUnknown16(1)In Diffuse Large B-cell Lymphoma (DLBCL), elevated anti-apoptotic BCL2-family proteins (e.g., MCL1, BCL2, BCLXL) and NF-κB subunits (RelA, RelB, cRel) confer poor prognosis. Heterogeneous expression, regulatory complexity, and redundancy offsetting the inhibition of individual proteins, complicate the assignment of targeted therapy. We combined flow cytometry 'fingerprinting', immunofluorescence imaging, and computational modeling to identify therapeutic vulnerabilities in DLBCL. The combined workflow predicted selective responses to BCL2 inhibition (venetoclax) and non-canonical NF-κB inhibition (Amgen16). Within the U2932 cell line we identified distinct resistance mechanisms to BCL2 inhibition in cellular sub-populations recapitulating intratumoral heterogeneity. Co-cultures with CD40L-Cell death & diseaseSystems biology-enabled targeting of NF-κΒ and BCL2 overcomes microenvironment-mediated BH3-mimetic resistance in DLBCL.PMC12357900R01 AI132731R01AI132731R01 AI12786723004MR/V009095/1Clark HKennedy EMitchell SPepper CHoffmann APepper AVaidehi Narayanan HStott LLiu YVareli ASimoes FJayawant EZhou HfalseSystems biology-enabled targeting of NF-κΒ and BCL2 overcomes microenvironment-mediated BH3-mimetic resistance in DLBCL.In Diffuse Large B-cell Lymphoma (DLBCL), elevated anti-apoptotic BCL2-family proteins (e.g., MCL1, BCL2, BCLXL) and NF-κB subunits (RelA, RelB, cRel) confer poor prognosis. Heterogeneous expression, regulatory complexity, and redundancy offsetting the inhibition of individual proteins, complicate the assignment of targeted therapy. We combined flow cytometry 'fingerprinting', immunofluorescence imaging, and computational modeling to identify therapeutic vulnerabilities in DLBCL. The combined workflow predicted selective responses to BCL2 inhibition (venetoclax) and non-canonical NF-κB inhibition (Amgen16). Within the U2932 cell line we identified distinct resistance mechanisms to BCL2 inhibition in cellular sub-populations recapitulating intratumoral heterogeneity. Co-cultures with CD40L-2025-01-01T00:00:00Z2025 Aug2026-07-15T05:45:12.807Z2026-06-29T03:19:15.743ZS-EPMC123579004081912610.1038/s41419-025-07942-0