{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T01:07:43Z","timestamp":1769044063429,"version":"3.49.0"},"reference-count":19,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2019,11,30]],"date-time":"2019-11-30T00:00:00Z","timestamp":1575072000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","award":["RUG 2014-6727"],"award-info":[{"award-number":["RUG 2014-6727"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","award":["Mandema Stipendium"],"award-info":[{"award-number":["Mandema Stipendium"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Expression of the anti-apoptotic B-cell lymphoma 2 (BCL-2) protein in patients with diffuse large B-cell lymphoma (DLBCL) strongly correlates with resistance to standard therapy with cyclophosphamide, vincristine, doxorubicin, prednisolone, and rituximab (R-CHOP). Although studies focus mainly on the contribution of BCL-2, here we also investigate the contribution of other anti-apoptotic proteins to CHOP-therapy resistance in DLBCL. Functional dynamic BCL-2 homology (BH)3 profiling was applied to DLBCL cell lines upon CHOP treatment or single CHOP compounds. Cell-specific anti-apoptotic dependencies were validated with corresponding BH3-mimetics. We found high expression of anti-apoptotic BCL-2, MCL-1, and BCL-XL in DLBCL cell lines and patients. CHOP treatment resulted in both enhanced and altered anti-apoptotic dependency. Enhanced sensitivity to different BH3-mimetics after CHOP treatment was confirmed in specific cell lines, indicating heterogeneity of CHOP-induced resistance in DLBCL. Analysis of single CHOP compounds demonstrated that similar changes could also be induced by doxorubicin or vincristine, providing evidence for clinical combination therapies of doxorubicin or vincristine with BH3-mimetics in DLBCL. In conclusion, we show for the first time that CHOP treatment induces increased anti-apoptotic dependency on MCL-1 and BCL-XL, and not just BCL-2. These results provide new perspectives for the treatment of CHOP-resistant DLBCL and underline the potential of BH3 profiling in predicting therapy outcomes.<\/jats:p>","DOI":"10.3390\/ijms20236036","type":"journal-article","created":{"date-parts":[[2019,12,2]],"date-time":"2019-12-02T10:50:45Z","timestamp":1575283845000},"page":"6036","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Heterogeneous Pattern of Dependence on Anti-Apoptotic BCL-2 Family Proteins upon CHOP Treatment in Diffuse Large B-Cell Lymphoma"],"prefix":"10.3390","volume":"20","author":[{"given":"Mathilde Rikje Willemijn","family":"de Jong","sequence":"first","affiliation":[{"name":"Department of Hematology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Myra","family":"Langendonk","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bart","family":"Reitsma","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2740-2873","authenticated-orcid":false,"given":"Marcel","family":"Nijland","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8894-2638","authenticated-orcid":false,"given":"Anke","family":"van den Berg","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuele","family":"Ammatuna","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lydia","family":"Visser","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5581-6950","authenticated-orcid":false,"given":"Tom","family":"van Meerten","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/cdd.2017.186","article-title":"BCL-2 family proteins: Changing partners in the dance towards death","volume":"25","author":"Kale","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/bs.acr.2017.11.001","article-title":"Bcl-2 Antiapoptotic Family Proteins and Chemoresistance in Cancer","volume":"137","author":"Maji","year":"2018","journal-title":"Adv. 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