Apoptotic Blocks in Primary Non-Hodgkin B Cell Lymphomas Identified by BH3 Profiling

• Main Authors: 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
• Format: Article
• Language: English
• Published: MDPI AG 2021-02-01
• Series: Cancers
• Subjects: NHL; BCL2; MCL1; apoptosis; DLBCL; BH3 profiling
• Online Access: https://www.mdpi.com/2072-6694/13/5/1002

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.