An oncogenic role for alternative NF-κB signaling in DLBCL revealed upon deregulated BCL6 expression

Cell Rep. 2015 May 5;11(5):715-26. doi: 10.1016/j.celrep.2015.03.059. Epub 2015 Apr 23.

Abstract

Diffuse large B cell lymphoma (DLBCL) is a complex disease comprising diverse subtypes and genetic profiles. Possibly because of the prevalence of genetic alterations activating canonical NF-κB activity, a role for oncogenic lesions that activate the alternative NF-κB pathway in DLBCL has remained elusive. Here, we show that deletion/mutation of TRAF3, a negative regulator of the alternative NF-κB pathway, occurs in ∼15% of DLBCLs and that it often coexists with BCL6 translocation, which prevents terminal B cell differentiation. Accordingly, in a mouse model constitutive activation of the alternative NF-κB pathway cooperates with BCL6 deregulation in DLBCL development. This work demonstrates a key oncogenic role for the alternative NF-κB pathway in DLBCL development.

Publication types

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

MeSH terms

  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Survival
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / metabolism
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-bcl-6
  • Signal Transduction
  • TNF Receptor-Associated Factor 3 / genetics
  • TNF Receptor-Associated Factor 3 / metabolism

Substances

  • Bcl6 protein, mouse
  • DNA-Binding Proteins
  • NF-kappa B
  • Proto-Oncogene Proteins c-bcl-6
  • TNF Receptor-Associated Factor 3
  • Protein-Serine-Threonine Kinases
  • NF-kappa B kinase