期刊
CANCER DISCOVERY
卷 4, 期 4, 页码 480-493出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-13-0915
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资金
- Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research
- NCI SPECS grant [UO1-CA 114778]
- Dr. Mildred Scheel Stiftung fur Krebsforschung (Deutsche Krebshilfe)
Constitutive activation of NF-kappa B is a hallmark of the activated B cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), owing to upstream signals from the B-cell receptor (BCR) and MYD88 pathways. The linear polyubiquitin chain assembly complex (LUBAC) attaches linear polyubiquitin chains to I kappa B kinase-gamma, a necessary event in some pathways that engage NF-kappa B. Two germline polymorphisms affecting the LUBAC subunit RNF31 are rare among healthy individuals (similar to 1%) but enriched in ABC DLBCL (7.8%). These polymorphisms alter RNF31 alpha-helices that mediate binding to the LUBAC subunit RBCK1, thereby increasing RNF31-RBCK1 association, LUBAC enzymatic activity, and NF-kappa B engagement. In the BCR pathway, LUBAC associates with the CARD11-MALT1-BCL10 adapter complex and is required for ABC DLBCL viability. A stapled RNF31 alpha-helical peptide based on the ABC DLBCL-associated Q622L polymorphism inhibited RNF31-RBCK1 binding, decreased NF-kappa B activation, and killed ABC DLBCL cells, credentialing this protein-protein interface as a therapeutic target. SIGNIFICANCE: We provide genetic, biochemical, and functional evidence that the LUBAC ubiquitin ligase is a therapeutic target in ABC DLBCL, the DLBCL subtype that is most refractory to current therapy. More generally, our findings highlight the role of rare germline-encoded protein variants in cancer pathogenesis. (C) 2014 AACR.
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