Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma

Cancer Cell. 2012 Jun 12;21(6):723-37. doi: 10.1016/j.ccr.2012.05.024.

Abstract

Knowledge of oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells while sparing normal cells. Lenalidomide is an active agent in the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), but its mechanism of action is unknown. Lenalidomide kills ABC DLBCL cells by augmenting interferon β (IFNβ) production, owing to the oncogenic MYD88 mutations in these lymphomas. In a cereblon-dependent fashion, lenalidomide downregulates IRF4 and SPIB, transcription factors that together prevent IFNβ production by repressing IRF7 and amplify prosurvival NF-κB signaling by transactivating CARD11. Blockade of B cell receptor signaling using the BTK inhibitor ibrutinib also downregulates IRF4 and consequently synergizes with lenalidomide in killing ABC DLBCLs, suggesting attractive therapeutic strategies.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Blotting, Western
  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Regulatory Networks / drug effects
  • Humans
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism
  • Interferon-beta / genetics
  • Interferon-beta / metabolism
  • Interferon-beta / pharmacology
  • Lenalidomide
  • Lymphoma, Large B-Cell, Diffuse / drug therapy*
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Peptide Hydrolases / genetics
  • Peptide Hydrolases / metabolism
  • Pyrazoles / administration & dosage
  • Pyrimidines / administration & dosage
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Thalidomide / administration & dosage
  • Thalidomide / analogs & derivatives
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Burden / drug effects*
  • Tumor Burden / genetics
  • Xenograft Model Antitumor Assays*

Substances

  • CRBN protein, human
  • DNA-Binding Proteins
  • Interferon Regulatory Factors
  • NF-kappa B
  • PCI 32765
  • Pyrazoles
  • Pyrimidines
  • Transcription Factors
  • interferon regulatory factor-4
  • SPIB protein, human
  • Thalidomide
  • Interferon-beta
  • Peptide Hydrolases
  • Lenalidomide

Associated data

  • GEO/GSE32456
  • GEO/GSE33012