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

Paradigms and Technologies
Methods Development

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.

Authors

Yang, Yibin; Shaffer, Arthur L; Emre, N C Tolga; Ceribelli, Michele; Zhang, Meili; Wright, George; Xiao, Wenming; Powell, John; Platig, John; Kohlhammer, Holger; Young, Ryan M; Zhao, Hong; Yang, Yandan; Xu, Weihong; Buggy, Joseph J; Balasubramanian, Sriram; Mathews, Lesley A; Shinn, Paul; Guha, Rajarshi; Ferrer-Alegre, Marc; Thomas, Craig; Waldmann, Thomas A; Staudt, Louis M;

Keywords

  • 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
  • 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

External Links