{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T15:23:15Z","timestamp":1792596195743,"version":"4.5.0"},"reference-count":65,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,2,28]],"date-time":"2021-02-28T00:00:00Z","timestamp":1614470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["299607"],"award-info":[{"award-number":["299607"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>To determine causes of apoptotic resistance, we analyzed 124 primary B cell NHL samples using BH3 profiling, a technique that measures the mitochondrial permeabilization upon exposure to synthetic BH3 peptides. Our cohort included samples from chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), high-grade B cell lymphoma with translocations in MYC and BCL2 (HGBL-DH), mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL). While a large number of our samples displayed appropriate responses to apoptosis-inducing peptides, pro-apoptotic functional defects, implicating BAX, BAK, BIM or BID, were seen in 32.4% of high-grade NHLs (12\/37) and in 3.4% of low-grade NHLs (3\/87, p &lt; 0.0001). The inhibition of single anti-apoptotic proteins induced apoptosis in only a few samples, however, the dual inhibition of BCL2 and MCL1 was effective in 83% of samples, indicating MCL1 was the most common cause of lack of response to the BCL2 inhibitor, venetoclax. We then profiled Toledo and OCI-Ly8 high-grade lymphoma cell lines to determine which drugs could reduce MCL1 expression and potentiate venetoclax responses. Doxorubicin and vincristine decreased levels of MCL1 and increased venetoclax-induced apoptosis (all p &lt; 0.05). Overall, in primary NHLs expressing BCL2 that have no defects in pro-apoptotic signaling, a poor response to venetoclax is primarily due to the presence of MCL1, which may be overcome by combining venetoclax with doxorubicin and vincristine-based chemotherapy or with other anti-microtubule inhibitors.<\/jats:p>","DOI":"10.3390\/cancers13051002","type":"journal-article","created":{"date-parts":[[2021,2,28]],"date-time":"2021-02-28T20:43:32Z","timestamp":1614545012000},"page":"1002","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Apoptotic Blocks in Primary Non-Hodgkin B Cell Lymphomas Identified by BH3 Profiling"],"prefix":"10.3390","volume":"13","author":[{"given":"Ryan N.","family":"Rys","sequence":"first","affiliation":[{"name":"Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada"},{"name":"Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia M.","family":"Wever","sequence":"additional","affiliation":[{"name":"Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada"},{"name":"Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6368-7474","authenticated-orcid":false,"given":"Dominique","family":"Geoffrion","sequence":"additional","affiliation":[{"name":"Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada"},{"name":"Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada"},{"name":"Department of Experimental Surgery, McGill University, Montreal, QC H3G 1A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Goncalves","sequence":"additional","affiliation":[{"name":"Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5810-0106","authenticated-orcid":false,"given":"Artin","family":"Ghassemian","sequence":"additional","affiliation":[{"name":"Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada"},{"name":"Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene","family":"Brailovski","sequence":"additional","affiliation":[{"name":"Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3327-1283","authenticated-orcid":false,"given":"Jeremy","family":"Ryan","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana","family":"Stoica","sequence":"additional","affiliation":[{"name":"Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9e","family":"H\u00e9bert","sequence":"additional","affiliation":[{"name":"Department of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"},{"name":"Division of Hematology-Oncology and Quebec Leukemia Cell Bank, Maisonneuve Rosemont Hospital, Montreal, QC H1T 2M4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Petrogiannis-Haliotis","sequence":"additional","affiliation":[{"name":"Division of Pathology, Jewish General Hospital, Montr\u00e9al, QC H3T 1E2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetlana","family":"Dmitrienko","sequence":"additional","affiliation":[{"name":"Division of Pathology, Jewish General Hospital, Montr\u00e9al, QC H3T 1E2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saul","family":"Frenkiel","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Jewish General Hospital, Montreal, QC H3T 1E2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5896-3200","authenticated-orcid":false,"given":"Annette","family":"Staiger","sequence":"additional","affiliation":[{"name":"Department of Pathology, Robert-Bosch Hospital, 70184 Stuttgart, Germany"},{"name":"Dr. Margarete-Fischer-Bosch-Institute of Clinical Pharmacology, University of T\u00fcbingen, 70376 Stuttgart, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"German","family":"Ott","sequence":"additional","affiliation":[{"name":"Department of Pathology, Robert-Bosch Hospital, 70184 Stuttgart, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Steidl","sequence":"additional","affiliation":[{"name":"Center for Lymphoid Cancer, BC Cancer, Vancouver, BC V5Z 1L3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W.","family":"Scott","sequence":"additional","affiliation":[{"name":"Center for Lymphoid Cancer, BC Cancer, Vancouver, BC V5Z 1L3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8264-822X","authenticated-orcid":false,"given":"Pierre","family":"Sesques","sequence":"additional","affiliation":[{"name":"Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"del Rincon","sequence":"additional","affiliation":[{"name":"Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada"},{"name":"Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koren K.","family":"Mann","sequence":"additional","affiliation":[{"name":"Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada"},{"name":"Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1993-9013","authenticated-orcid":false,"given":"Anthony","family":"Letai","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie A.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada"},{"name":"Department of Medicine, McGill 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