<i>SETD1B</i> mutations confer apoptosis resistance and BCL2 independence in B cell lymphoma
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.
Authors
- Elisa de Stanchina (ORCID: https://orcid.org/0000-0002-3873-315X)
- Ana Portelinha (ORCID: https://orcid.org/0000-0003-0518-9554)
- Sagarajit Mohanty (ORCID: https://orcid.org/0000-0001-7935-7798)
- Ari Melnick (ORCID: https://orcid.org/0000-0002-8074-2287)
- Ahmet Doǧan (ORCID: https://orcid.org/0000-0001-6576-5256)
- Neeraj K. Aryal (ORCID: https://orcid.org/0000-0002-4643-7078)
- Marjan Berishaj (ORCID: https://orcid.org/0009-0006-1872-6522)
- Man Jiang (ORCID: https://orcid.org/0000-0003-1818-7427)
- Alexander N. Gorelick (ORCID: https://orcid.org/0000-0001-6736-8246)
- Anas Younes (ORCID: https://orcid.org/0000-0002-0001-4133)
- Shenqiu Wang (ORCID: https://orcid.org/0000-0002-0601-2075)
- Omid Tavana (ORCID: https://orcid.org/0000-0001-8401-4546)
- Jiayu Wen (ORCID: https://orcid.org/0000-0003-1249-6456)
- Jude Fitzgibbon
- James A. Heward (ORCID: https://orcid.org/0000-0002-4022-1532)
- Soumya Sharma (ORCID: https://orcid.org/0009-0003-7650-3720)
- S. Parsa
- Chunying Zhao
- Hans-Guido Wendel
Institutions
- Australian National University (AU)
- Memorial Sloan Kettering Cancer Center (US)
- Australian Research Council (AU)
- NewYork–Presbyterian Hospital (US)
- Harvard University (US)
- Cornell University (US)
- New York Hospital Queens (US)
- Presbyterian Hospital (US)
- e-Therapeutics (United Kingdom) (GB)
- AstraZeneca (United States) (US)
- Weill Cornell Medicine (US)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2024-09-05
- DOI
- https://doi.org/10.1084/jem.20231143
- Citations
- 9
- Primary Topic
- Cancer-related gene regulation
- Type
- article
- Field-Weighted Citation Impact
- 2.10
Funders
- Lymphoma Research Foundation
- Samuel Waxman Cancer Research Foundation
- Chemotherapy Foundation
- AstraZeneca
- Leukemia and Lymphoma Society
- Memorial Sloan-Kettering Cancer Center
- Geoffrey Beene Cancer Research Center
- National Institutes of Health
- National Cancer Institute