| Autor: |
Louis M. Staudt, Federico Bernal, Kazuhiro Iwai, Michael J. Kruhlak, Adrian Wiestner, Wing C. Chan, Dennis D. Weisenburger, James R. Cook, Raymond R. Tubbs, Rita M. Braziel, Erlend B. Smeland, Jan Delabie, Elaine S. Jaffe, Elias Campo, Lisa M. Rimsza, Joseph M. Connors, Randy D. Gascoyne, German Ott, Andreas Rosenwald, Weihong Xu, Yandan Yang, Hong Zhao, George W. Wright, Michele Ceribelli, Wenming Xiao, Amanda Whiting, Joseph Mitala, Roland Schmitz, Yibin Yang |
| Rok vydání: |
2023 |
| DOI: |
10.1158/2159-8290.c.6546105.v1 |
| Popis: |
Constitutive activation of NF-κB 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 IκB kinase-γ, a necessary event in some pathways that engage NF-κB. Two germline polymorphisms affecting the LUBAC subunit RNF31 are rare among healthy individuals (∼1%) but enriched in ABC DLBCL (7.8%). These polymorphisms alter RNF31 α-helices that mediate binding to the LUBAC subunit RBCK1, thereby increasing RNF31–RBCK1 association, LUBAC enzymatic activity, and NF-κB engagement. In the BCR pathway, LUBAC associates with the CARD11–MALT1–BCL10 adapter complex and is required for ABC DLBCL viability. A stapled RNF31 α-helical peptide based on the ABC DLBCL–associated Q622L polymorphism inhibited RNF31–RBCK1 binding, decreased NF-κB 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. Cancer Discov; 4(4); 480–93. ©2014 AACR.See related commentary by Grumati and Dikic, p. 394This article is highlighted in the In This Issue feature, p. 377 |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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