Journal-Based CME: SETD1B Mutations Confer Apoptosis Resistance and BCL2 Independence in B Cell Lymphoma

Thursday, September 5, 2024, 10:00 AM - Sunday, September 5, 2027, 11:00 PM

This Journal-Based CME activity consists of a full-text article that is free to read, a multiple-choice question test, and an evaluation/self-assessment. Learners are tested on their comprehension of the key concepts, with the objective of enriching their clinical practice and patient care through better understanding of scientific advances and new techniques in the fields covered by Journal of Experimental Medicine (JEM). 

Questions for this complimentary, online-only activity have been designed by JEM editors in collaboration with the article authors. Each CME activity should take approximately 1 hour to complete.

The article selected for this activity is “SETD1B mutations confer apoptosis resistance and BCL2 independence in B cell lymphoma,” by Ana Portelinha, Shenqiu Wang, Sara Parsa, Man Jiang, Alexander N. Gorelick, Sagarajit Mohanty, Soumya Sharma, Elisa de Stanchina, Marjan Berishaj, Chunying Zhao, James Heward, Neeraj K Arya, Omid Tavana, Jiayu Wen, Jude Fitzgibbon, Ahmet Dogan, Anas Younes, Ari M. Melnick, and Hans-Guido Wendel at Memorial Sloan-Kettering Cancer Center in New York, NY.

Article Abstract

The translocation t(14;18) activates BCL2 and is considered the initiating genetic lesion in most follicular lymphomas (FL). Surprisingly, FL patients fail to respond to the BCL2 inhibitor, Venetoclax. We show that mutations and deletions affecting the histone lysine methyltransferase SETD1B (KMT2G) occur in 7% of FLs and 16% of diffuse large B cell lymphomas (DLBCL). Deficiency in SETD1B confers striking resistance to Venetoclax and an experimental MCL-1 inhibitor. SETD1B also acts as a tumor suppressor and cooperates with the loss of KMT2D in lymphoma development in vivo. Consistently, loss of SETD1B in human lymphomas typically coincides with loss of KMT2D. Mechanistically, SETD1B is required for the expression of several proapoptotic BCL2 family proteins. Conversely, inhibitors of the KDM5 histone H3K4 demethylases restore BIM and BIK expression and synergize with Venetoclax in SETD1B-deficient lymphomas. These results establish SETD1B as an epigenetic regulator of cell death and reveal a pharmacological strategy to augment Venetoclax sensitivity in lymphoma.

About Journal of Experimental Medicine (JEM) and CME Activities

JEM publishes peer-reviewed papers within the field of medical biology, providing novel conceptual insights into immunology, cancer biology, neuroscience, inflammation, vascular biology, microbial pathogenesis, and stem cell biology. These studies range from original findings on all aspects of disease pathogenesis to novel therapeutic approaches. Articles designated for Journal-Based CME have been selected by JEM editors for their clinical relevance and ability to address practice-based gaps.

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Memorial Sloan Kettering Cancer Center, the Journal of Experimental Medicine (JEM) and Rockefeller University Press. Memorial Sloan Kettering Cancer Center is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

AMA Credit Designation Statement

Memorial Sloan Kettering Cancer Center designates this enduring material for a maximum of 1 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

 

Recorded/Review Date: September 5, 2024; Original Release Date: September 25, 2024; Termination Date: September 25, 2027

Mitigation of Relevant Financial Relationships

Memorial Sloan Kettering Cancer Center adheres to the ACCME’s Standards for Integrity and Independence in Accredited Continuing Education. Any individuals in a position to control the content of a CE activity, including faculty, planners, reviewers or others are required to disclose all relevant financial relationships with ineligible entities (commercial interests). All relevant conflicts of interest have been mitigated prior to the commencement of the activity.