title: Targeting Non-proteolytic Protein Ubiquitination for the Treatment of Diffuse Large B Cell Lymphoma.
abstract: Chronic active B cell receptor (BCR) signaling, a hallmark of the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), engages the CARD11-MALT1-BCL10 (CBM) adapter complex to activate IκB kinase (IKK) and the classical NF-κB pathway. Here we show that the CBM complex includes the E3 ubiquitin ligases cIAP1 and cIAP2, which are essential mediators of BCR-dependent NF-κB activity in ABC DLBCL. cIAP1/2 attach K63-linked polyubiquitin chains on themselves and on BCL10, resulting in the recruitment of IKK and the linear ubiquitin chain ligase LUBAC, which is essential for IKK activation. SMAC mimetics target cIAP1/2 for destruction, and consequently suppress NF-κB and selectively kill BCR-dependent ABC DLBCL lines, supporting their clinical evaluation in patients with ABC DLBCL.
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 4N115, Bethesda, MD 20892, USA.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 4N115, Bethesda, MD 20892, USA.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Kelly
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 4N115, Bethesda, MD 20892, USA.
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Shaffer
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 4N115, Bethesda, MD 20892, USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Schmitz
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 4N115, Bethesda, MD 20892, USA.
authors.forename: Hee Min
authors.initials: HM
authors.lastname: Yoo
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 4N115, Bethesda, MD 20892, USA.
authors.forename: Xinyue
authors.initials: X
authors.lastname: Liu
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 4N115, Bethesda, MD 20892, USA.
authors.forename: Da Wei
authors.initials: DW
authors.lastname: Huang
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 4N115, Bethesda, MD 20892, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Webster
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 4N115, Bethesda, MD 20892, USA.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Young
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 4N115, Bethesda, MD 20892, USA.
authors.forename: Masao
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 4N115, Bethesda, MD 20892, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Ceribelli
authors.affiliation: Biometric Research Branch, Division of Cancer Diagnosis and Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: George W
authors.initials: GW
authors.lastname: Wright
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 4N115, Bethesda, MD 20892, USA.
authors.forename: Yandan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 4N115, Bethesda, MD 20892, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 4N115, Bethesda, MD 20892, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Yu
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 4N115, Bethesda, MD 20892, USA.
authors.forename: Weihong
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
authors.affiliation: British Columbia Cancer Agency, Vancouver, BC V5Z 4E6, Canada.
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.affiliation: Hospital Clinic, University of Barcelona, 08036 Barcelona, Spain.
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.affiliation: Department of Pathology, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology, 70376 Stuttgart, Germany.
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.affiliation: Department of Pathology, University Health Network, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Jan
authors.initials: J
authors.lastname: Delabie
authors.affiliation: Department of Pathology, University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Rimsza
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 4N115, Bethesda, MD 20892, USA. Electronic address: lstaudt@mail.nih.gov.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D000074018:B-Cell CLL-Lymphoma 10 Protein; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism; D064113:CRISPR-Cas Systems; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology / Q000627:therapeutic use*; D004789:Enzyme Activation; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry; D016403:Lymphoma, Large B-Cell, Diffuse / Q000145:classification / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D024101:Mitochondrial Proteins / Q000737:chemistry; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D046912:Multiprotein Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D054875:Ubiquitination / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D019086:Bridged Bicyclo Compounds, Heterocyclic; D053468:CARD Signaling Adaptor Proteins; C412403:DIABLO protein, human; D004151:Dipeptides; D007211:Indoles; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011947:Receptors, Antigen, B-Cell; C533467:SM 164; D014230:Triazoles; C582429:birinapant; C494833:BIRC2 protein, human; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D051550:I-kappa B Kinase; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; C426242:CARD11 protein, human; D006162:Guanylate Cyclase