Targeting Non-proteolytic Protein Ubiquitination for the Treatment of Diffuse Large B Cell Lymphoma

Cancer Cell. 2016 Apr 11;29(4):494-507. doi: 10.1016/j.ccell.2016.03.006.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Apoptosis Regulatory Proteins
  • B-Cell CLL-Lymphoma 10 Protein
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / metabolism
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic / therapeutic use*
  • CARD Signaling Adaptor Proteins / metabolism
  • CRISPR-Cas Systems
  • Caspases / metabolism
  • Cell Line, Tumor
  • Dipeptides / pharmacology
  • Dipeptides / therapeutic use*
  • Enzyme Activation
  • Gene Dosage
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Guanylate Cyclase / metabolism
  • Humans
  • I-kappa B Kinase / metabolism
  • Indoles / pharmacology
  • Indoles / therapeutic use*
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / physiology*
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Lymphoma, Large B-Cell, Diffuse / classification
  • Lymphoma, Large B-Cell, Diffuse / drug therapy*
  • Lymphoma, Large B-Cell, Diffuse / metabolism
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mitochondrial Proteins / chemistry
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • Multiprotein Complexes / metabolism
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neoplasm Proteins / physiology*
  • Protein Processing, Post-Translational / drug effects*
  • Receptors, Antigen, B-Cell / metabolism
  • Triazoles / pharmacology
  • Triazoles / therapeutic use*
  • Ubiquitin-Protein Ligases / antagonists & inhibitors
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / physiology*
  • Ubiquitination / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • B-Cell CLL-Lymphoma 10 Protein
  • BCL10 protein, human
  • Bridged Bicyclo Compounds, Heterocyclic
  • CARD Signaling Adaptor Proteins
  • DIABLO protein, human
  • Dipeptides
  • Indoles
  • Inhibitor of Apoptosis Proteins
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Multiprotein Complexes
  • NF-kappa B
  • Neoplasm Proteins
  • Receptors, Antigen, B-Cell
  • SM 164
  • Triazoles
  • birinapant
  • BIRC2 protein, human
  • BIRC3 protein, human
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Ubiquitin-Protein Ligases
  • I-kappa B Kinase
  • Caspases
  • MALT1 protein, human
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • CARD11 protein, human
  • Guanylate Cyclase