Pathogenic role of B-cell receptor signaling and canonical NF-κB activation in mantle cell lymphoma

Blood. 2016 Jul 7;128(1):82-92. doi: 10.1182/blood-2015-11-681460. Epub 2016 Apr 28.

Abstract

To interrogate signaling pathways activated in mantle cell lymphoma (MCL) in vivo, we contrasted gene expression profiles of 55 tumor samples isolated from blood and lymph nodes from 43 previously untreated patients with active disease. In addition to lymph nodes, MCL often involves blood, bone marrow, and spleen and is incurable for most patients. Recently, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib demonstrated important clinical activity in MCL. However, the role of specific signaling pathways in the lymphomagenesis of MCL and the biologic basis for ibrutinib sensitivity of these tumors are unknown. Here, we demonstrate activation of B-cell receptor (BCR) and canonical NF-κB signaling specifically in MCL cells in the lymph node. Quantification of BCR signaling strength, reflected in the expression of BCR regulated genes, identified a subset of patients with inferior survival after cytotoxic therapy. Tumor proliferation was highest in the lymph node and correlated with the degree of BCR activation. A subset of leukemic tumors showed active BCR and NF-κB signaling apparently independent of microenvironmental support. In one of these samples, we identified a novel somatic mutation in RELA (E39Q). This sample was resistant to ibrutinib-mediated inhibition of NF-κB and apoptosis. In addition, we identified germ line variants in genes encoding regulators of the BCR and NF-κB pathway previously implicated in lymphomagenesis. In conclusion, BCR signaling, activated in the lymph node microenvironment in vivo, appears to promote tumor proliferation and survival and may explain the sensitivity of this lymphoma to BTK inhibitors.

Publication types

  • Clinical Trial

MeSH terms

  • Amino Acid Substitution
  • Apoptosis* / drug effects
  • Apoptosis* / genetics
  • Disease-Free Survival
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Humans
  • Lymphoma, Mantle-Cell* / drug therapy
  • Lymphoma, Mantle-Cell* / genetics
  • Lymphoma, Mantle-Cell* / metabolism
  • Lymphoma, Mantle-Cell* / mortality
  • Male
  • Mutation, Missense*
  • Pyrazoles / administration & dosage*
  • Pyrimidines / administration & dosage*
  • Receptors, Antigen, B-Cell / genetics
  • Receptors, Antigen, B-Cell / metabolism*
  • Signal Transduction* / drug effects
  • Signal Transduction* / genetics
  • Survival Rate
  • Transcription Factor RelA* / genetics
  • Transcription Factor RelA* / metabolism

Substances

  • Pyrazoles
  • Pyrimidines
  • RELA protein, human
  • Receptors, Antigen, B-Cell
  • Transcription Factor RelA
  • ibrutinib