Systems biology-enabled targeting of NF-κΒ and BCL2 overcomes microenvironment-mediated BH3-mimetic resistance in DLBCL
Abstract 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, com...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07942-0 |
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| author | Aimilia Vareli Haripriya Vaidehi Narayanan Heather Clark Eleanor Jayawant Hui Zhou Yi Liu Emma Kennedy Lauren Stott Fabio Simoes Alexander Hoffmann Andrea Pepper Chris Pepper Simon Mitchell |
| author_facet | Aimilia Vareli Haripriya Vaidehi Narayanan Heather Clark Eleanor Jayawant Hui Zhou Yi Liu Emma Kennedy Lauren Stott Fabio Simoes Alexander Hoffmann Andrea Pepper Chris Pepper Simon Mitchell |
| author_sort | Aimilia Vareli |
| collection | DOAJ |
| description | Abstract 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-expressing stromal cells, mimicking the tumor microenvironment (TME), induced resistance to BCL2 and BCLXL targeting BH3-mimetics via cell-type specific upregulation of BCLXL or MCL1. Computational models, validated experimentally, showed that basal NF-κB activation determined whether CD40 activation drove BH3-mimetic resistance through upregulation of RelB and BCLXL, or cRel and MCL1. High basal NF-κB activity could be overcome by inhibiting BTK to resensitize cells to BH3-mimetics in CD40L co-culture. Importantly, non-canonical NF-κB inhibition overcame heterogeneous compensatory BCL2 upregulation, restoring sensitivity to both BCL2- and BCLXL-targeting BH3-mimetics. Combined molecular fingerprinting and computational modelling provides a strategy for the precision use of BH3-mimetics and NF-κB inhibitors in DLBCL. |
| format | Article |
| id | doaj-art-60eb283a08ab4d8dba2fe6da69f2a5c5 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-60eb283a08ab4d8dba2fe6da69f2a5c52025-08-20T03:43:45ZengNature Publishing GroupCell Death and Disease2041-48892025-08-0116111210.1038/s41419-025-07942-0Systems biology-enabled targeting of NF-κΒ and BCL2 overcomes microenvironment-mediated BH3-mimetic resistance in DLBCLAimilia Vareli0Haripriya Vaidehi Narayanan1Heather Clark2Eleanor Jayawant3Hui Zhou4Yi Liu5Emma Kennedy6Lauren Stott7Fabio Simoes8Alexander Hoffmann9Andrea Pepper10Chris Pepper11Simon Mitchell12Department of Clinical and Experimental Medicine, Brighton and Sussex Medical School, University of Brighton and University of SussexSignaling Systems Laboratory, Department of Microbiology, Immunology, and Molecular Genetics, and Institute for Quantitative and Computational Biosciences, University of California, Los AngelesDepartment of Clinical and Experimental Medicine, Brighton and Sussex Medical School, University of Brighton and University of SussexDepartment of Clinical and Experimental Medicine, Brighton and Sussex Medical School, University of Brighton and University of SussexDeepKinase BiotechnologiesDeepKinase BiotechnologiesDepartment of Clinical and Experimental Medicine, Brighton and Sussex Medical School, University of Brighton and University of SussexDepartment of Clinical and Experimental Medicine, Brighton and Sussex Medical School, University of Brighton and University of SussexDepartment of Clinical and Experimental Medicine, Brighton and Sussex Medical School, University of Brighton and University of SussexSignaling Systems Laboratory, Department of Microbiology, Immunology, and Molecular Genetics, and Institute for Quantitative and Computational Biosciences, University of California, Los AngelesDepartment of Clinical and Experimental Medicine, Brighton and Sussex Medical School, University of Brighton and University of SussexDepartment of Clinical and Experimental Medicine, Brighton and Sussex Medical School, University of Brighton and University of SussexDepartment of Clinical and Experimental Medicine, Brighton and Sussex Medical School, University of Brighton and University of SussexAbstract 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-expressing stromal cells, mimicking the tumor microenvironment (TME), induced resistance to BCL2 and BCLXL targeting BH3-mimetics via cell-type specific upregulation of BCLXL or MCL1. Computational models, validated experimentally, showed that basal NF-κB activation determined whether CD40 activation drove BH3-mimetic resistance through upregulation of RelB and BCLXL, or cRel and MCL1. High basal NF-κB activity could be overcome by inhibiting BTK to resensitize cells to BH3-mimetics in CD40L co-culture. Importantly, non-canonical NF-κB inhibition overcame heterogeneous compensatory BCL2 upregulation, restoring sensitivity to both BCL2- and BCLXL-targeting BH3-mimetics. Combined molecular fingerprinting and computational modelling provides a strategy for the precision use of BH3-mimetics and NF-κB inhibitors in DLBCL.https://doi.org/10.1038/s41419-025-07942-0 |
| spellingShingle | Aimilia Vareli Haripriya Vaidehi Narayanan Heather Clark Eleanor Jayawant Hui Zhou Yi Liu Emma Kennedy Lauren Stott Fabio Simoes Alexander Hoffmann Andrea Pepper Chris Pepper Simon Mitchell Systems biology-enabled targeting of NF-κΒ and BCL2 overcomes microenvironment-mediated BH3-mimetic resistance in DLBCL Cell Death and Disease |
| title | Systems biology-enabled targeting of NF-κΒ and BCL2 overcomes microenvironment-mediated BH3-mimetic resistance in DLBCL |
| title_full | Systems biology-enabled targeting of NF-κΒ and BCL2 overcomes microenvironment-mediated BH3-mimetic resistance in DLBCL |
| title_fullStr | Systems biology-enabled targeting of NF-κΒ and BCL2 overcomes microenvironment-mediated BH3-mimetic resistance in DLBCL |
| title_full_unstemmed | Systems biology-enabled targeting of NF-κΒ and BCL2 overcomes microenvironment-mediated BH3-mimetic resistance in DLBCL |
| title_short | Systems biology-enabled targeting of NF-κΒ and BCL2 overcomes microenvironment-mediated BH3-mimetic resistance in DLBCL |
| title_sort | systems biology enabled targeting of nf κβ and bcl2 overcomes microenvironment mediated bh3 mimetic resistance in dlbcl |
| url | https://doi.org/10.1038/s41419-025-07942-0 |
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