Data from Essential Role of the Linear Ubiquitin Chain Assembly Complex in Lymphoma Revealed by Rare Germline Polymorphisms

Abstract

<div>Abstract<p>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.</p><p><b>Significance:</b> 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. <i>Cancer Discov; 4(4); 480–93. ©2014 AACR</i>.</p><p>See related commentary by Grumati and Dikic, p. 394</p><p>This article is highlighted in the In This Issue feature, p. 377</p></div>