SETD1B mutations confer apoptosis resistance and BCL2 independence in B cell lymphoma Journal Article
| Authors: | Portelinha, A.; Wang, S.; Parsa, S.; Jiang, M.; Gorelick, A. N.; Mohanty, S.; Sharma, S.; de Stanchina, E.; Berishaj, M.; Zhao, C.; Heward, J.; Aryal, N. K.; Tavana, O.; Wen, J.; Fitzgibbon, J.; Dogan, A.; Younes, A.; Melnick, A. M.; Wendel, H. G. |
| Article Title: | SETD1B mutations confer apoptosis resistance and BCL2 independence in B cell lymphoma |
| 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. © 2024 Portelinha et al. |
| Keywords: | dna binding protein; genetics; mutation; dna-binding proteins; mouse; animal; metabolism; animals; mice; protein bcl 2; apoptosis; neoplasm proteins; drug resistance; pathology; drug resistance, neoplasm; cell line, tumor; b cell lymphoma; lymphoma, b-cell; histone-lysine n-methyltransferase; sulfonamide; sulfonamides; tumor protein; tumor cell line; lymphoma, large b-cell, diffuse; fused heterocyclic rings; proto-oncogene proteins c-bcl-2; histone lysine methyltransferase; diffuse large b cell lymphoma; humans; human; venetoclax; bcl2 protein, human; bridged bicyclo compounds, heterocyclic; kmt2d protein, human |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 221 |
| Issue: | 10 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2024-10-07 |
| Start Page: | e20231143 |
| Language: | English |
| DOI: | 10.1084/jem.20231143 |
| PUBMED: | 39235528 |
| PROVIDER: | scopus |
| PMCID: | PMC11380151 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Hans-Guido Wendel -- Source: Scopus |
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