Apoptotic Blocks in Primary Non-Hodgkin B Cell Lymphomas Identified by BH3 Profiling
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...
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2021-02-01
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doaj-123070e75a91428ea3297b90a91d88782021-03-01T00:00:49ZengMDPI AGCancers2072-66942021-02-01131002100210.3390/cancers13051002Apoptotic Blocks in Primary Non-Hodgkin B Cell Lymphomas Identified by BH3 ProfilingRyan N. Rys0Claudia M. Wever1Dominique Geoffrion2Christophe Goncalves3Artin Ghassemian4Eugene Brailovski5Jeremy Ryan6Liliana Stoica7Josée Hébert8Tina Petrogiannis-Haliotis9Svetlana Dmitrienko10Saul Frenkiel11Annette Staiger12German Ott13Christian Steidl14David W. Scott15Pierre Sesques16Sonia del Rincon17Koren K. Mann18Anthony Letai19Nathalie A. Johnson20Department of Physiology, McGill University, Montreal, QC H3G 1Y6, CanadaLady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, CanadaLady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, CanadaLady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, CanadaLady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, CanadaDepartment of Medicine, McGill University, Montreal, QC H4A 3J1, CanadaDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USALady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, CanadaDepartment of Medicine, Université de Montréal, Montreal, QC H3T 1J4, CanadaDivision of Pathology, Jewish General Hospital, Montréal, QC H3T 1E2, CanadaDivision of Pathology, Jewish General Hospital, Montréal, QC H3T 1E2, CanadaDepartment of Otolaryngology-Head and Neck Surgery, Jewish General Hospital, Montreal, QC H3T 1E2, CanadaDepartment of Pathology, Robert-Bosch Hospital, 70184 Stuttgart, GermanyDepartment of Pathology, Robert-Bosch Hospital, 70184 Stuttgart, GermanyCenter for Lymphoid Cancer, BC Cancer, Vancouver, BC V5Z 1L3, CanadaCenter for Lymphoid Cancer, BC Cancer, Vancouver, BC V5Z 1L3, CanadaLady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, CanadaLady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, CanadaLady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, CanadaDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USALady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, CanadaTo 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 <i>MYC</i> and <i>BCL2</i> (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, <i>p</i> < 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 <i>p</i> < 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.https://www.mdpi.com/2072-6694/13/5/1002NHLBCL2MCL1apoptosisDLBCLBH3 profiling |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ryan N. Rys Claudia M. Wever Dominique Geoffrion Christophe Goncalves Artin Ghassemian Eugene Brailovski Jeremy Ryan Liliana Stoica Josée Hébert Tina Petrogiannis-Haliotis Svetlana Dmitrienko Saul Frenkiel Annette Staiger German Ott Christian Steidl David W. Scott Pierre Sesques Sonia del Rincon Koren K. Mann Anthony Letai Nathalie A. Johnson |
spellingShingle |
Ryan N. Rys Claudia M. Wever Dominique Geoffrion Christophe Goncalves Artin Ghassemian Eugene Brailovski Jeremy Ryan Liliana Stoica Josée Hébert Tina Petrogiannis-Haliotis Svetlana Dmitrienko Saul Frenkiel Annette Staiger German Ott Christian Steidl David W. Scott Pierre Sesques Sonia del Rincon Koren K. Mann Anthony Letai Nathalie A. Johnson Apoptotic Blocks in Primary Non-Hodgkin B Cell Lymphomas Identified by BH3 Profiling Cancers NHL BCL2 MCL1 apoptosis DLBCL BH3 profiling |
author_facet |
Ryan N. Rys Claudia M. Wever Dominique Geoffrion Christophe Goncalves Artin Ghassemian Eugene Brailovski Jeremy Ryan Liliana Stoica Josée Hébert Tina Petrogiannis-Haliotis Svetlana Dmitrienko Saul Frenkiel Annette Staiger German Ott Christian Steidl David W. Scott Pierre Sesques Sonia del Rincon Koren K. Mann Anthony Letai Nathalie A. Johnson |
author_sort |
Ryan N. Rys |
title |
Apoptotic Blocks in Primary Non-Hodgkin B Cell Lymphomas Identified by BH3 Profiling |
title_short |
Apoptotic Blocks in Primary Non-Hodgkin B Cell Lymphomas Identified by BH3 Profiling |
title_full |
Apoptotic Blocks in Primary Non-Hodgkin B Cell Lymphomas Identified by BH3 Profiling |
title_fullStr |
Apoptotic Blocks in Primary Non-Hodgkin B Cell Lymphomas Identified by BH3 Profiling |
title_full_unstemmed |
Apoptotic Blocks in Primary Non-Hodgkin B Cell Lymphomas Identified by BH3 Profiling |
title_sort |
apoptotic blocks in primary non-hodgkin b cell lymphomas identified by bh3 profiling |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2021-02-01 |
description |
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 <i>MYC</i> and <i>BCL2</i> (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, <i>p</i> < 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 <i>p</i> < 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. |
topic |
NHL BCL2 MCL1 apoptosis DLBCL BH3 profiling |
url |
https://www.mdpi.com/2072-6694/13/5/1002 |
work_keys_str_mv |
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