NF-κB activation in chronic lymphocytic leukemia: A point of convergence of external triggers and intrinsic lesions

Semin Cancer Biol. 2016 Aug;39:40-8. doi: 10.1016/j.semcancer.2016.07.005. Epub 2016 Aug 1.


The nuclear factor-κB (NF-κB) pathway is constitutively activated in chronic lymphocytic leukemia (CLL) patients, and hence plays a major role in disease development and evolution. In contrast to many other mature B-cell lymphomas, only a few recurrently mutated genes involved in canonical or non-canonical NF-κB activation have been identified in CLL (i.e. BIRC3, MYD88 and NFKBIE mutations) and often at a low frequency. On the other hand, CLL B cells seem 'addicted' to the tumor microenvironment for their survival and proliferation, which is primarily mediated by interaction through a number of cell surface receptors, e.g. the B-cell receptor (BcR), Toll-like receptors and CD40, that in turn activate downstream NF-κB. The importance of cell-extrinsic triggering for CLL pathophysiology was recently also highlighted by the clinical efficacy of novel drugs targeting microenvironmental interactions through the inhibition of BcR signaling. In other words, CLL can be considered a prototype disease for studying the intricate interplay between external triggers and intrinsic aberrations and their combined impact on disease evolution. In this review, we will discuss the current understanding of mechanisms underlying NF-κB deregulation in CLL, including micro-environmental, genetic and epigenetic events, and summarize data generated in murine models resembling human CLL. Finally, we will also discuss different strategies undertaken to intervene with the NF-κB pathway and its upstream mediators.

Keywords: Chronic lymphocytic leukemia; Gene mutations; Microenvironment; NF-κB.

Publication types

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

MeSH terms

  • Animals
  • Baculoviral IAP Repeat-Containing 3 Protein / genetics
  • Baculoviral IAP Repeat-Containing 3 Protein / metabolism
  • Epigenesis, Genetic
  • Humans
  • Leukemia, Experimental / metabolism
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
  • Mice
  • Molecular Targeted Therapy / methods
  • Mutation
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Signal Transduction
  • Toll-Like Receptors / metabolism
  • Tumor Microenvironment


  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Toll-Like Receptors
  • BIRC3 protein, human
  • Baculoviral IAP Repeat-Containing 3 Protein