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Cancer Discov. 2014 Apr;4(4):480-93. doi: 10.1158/2159-8290.CD-13-0915. Epub 2014 Feb 3.

Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms.

Author information

1
1Lymphoid Malignancies Branch, 2Laboratory of Pathology, 3Experimental Immunology Branch, Center for Cancer Research; 4Biometric Research Branch, DCTD, National Cancer Institute; 5Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland; 6Department of Pathology, University of Arizona, Tucson, Arizona; 7Oregon Health and Science University, Portland, Oregon; 8Cleveland Clinic Pathology and Laboratory Medicine Institute, Cleveland, Ohio; 9Department of Pathology, City of Hope National Medical Center, Duarte, California; 10Departments of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska; 11Department of Pathology, University of Würzburg, Würzburg; 12Department of Clinical Pathology, Robert-Bosch-Krankenhaus; 13Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology, Stuttgart, Germany; 14British Columbia Cancer Agency, Vancouver, British Columbia, Canada; 15Hospital Clinic, University of Barcelona, Barcelona, Spain; 16Pathology Clinic, 17Institute for Cancer Research, Rikshospitalet University Hospital; 18Center for Cancer Biomedicine, Faculty Division of the Norwegian Radium Hospital, University of Oslo, Oslo, Norway; and 19Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Abstract

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.

PMID:
24491438
PMCID:
PMC3992927
DOI:
10.1158/2159-8290.CD-13-0915
[Indexed for MEDLINE]
Free PMC Article

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