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.
SETD1B mutations confer apoptosis resistance and BCL2 independence in B cell lymphoma
A. Portelinha, S. Wang, and S. Parsa contributed equally to this paper.
Disclosures: N.K. Aryal works for AstraZeneca and may own stocks of the company. O. Tavana reported personal fees from AstraZeneca outside the submitted work; and being an employee and shareholder of AstraZeneca. A. Dogan reported research support for AstraZeneca, not related to this work. A. Younes reported being currently employed by AstraZeneca. A.M. Melnick reported grants from Janssen, Daiichi Sankyo, Epizyme, AstraZeneca, and Treeline Biosciences during the conduct of the study; and personal fees from Treeline Biosciences and Ipsen outside the submitted work. H-.G. Wendel reported grants from AstraZeneca during the conduct of the study. No other disclosures were reported.
