Frequent down regulation of the tumor suppressor gene a20 in multiple myeloma

PLoS One. 2015 Apr 9;10(4):e0123922. doi: 10.1371/journal.pone.0123922. eCollection 2015.

Abstract

Multiple myeloma (MM) is a malignant clonal expansion of plasma cells in the bone marrow and belongs to the mature B-cell neoplams. The pathogenesis of MM is associated with constitutive NF-κB activation. However, genetic alterations causing constitutive NF-κB activation are still incompletely understood. Since A20 (TNFAIP3) is a suppressor of the NF-κB pathway and is frequently inactivated in various lymphoid malignancies, we investigated the genetic and epigenetic properties of A20 in MM. In total, of 46 patient specimens analyzed, 3 single base pair exchanges, 2 synonymous mutations and one missense mutation were detected by direct sequencing. Gene copy number analysis revealed a reduced A20 gene copy number in 8 of 45 (17.7%) patients. Furthermore, immunohistochemical staining confirmed that A20 expression correlates with the reduction of A20 gene copy number. These data suggest that A20 contributes to tumor formation in a significant fraction of myeloma patients.

MeSH terms

  • Apoptosis / genetics
  • Carcinogenesis / genetics*
  • DNA-Binding Proteins / biosynthesis*
  • DNA-Binding Proteins / genetics
  • Gene Dosage / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intracellular Signaling Peptides and Proteins / biosynthesis*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Multiple Myeloma / genetics*
  • Multiple Myeloma / pathology
  • Mutation, Missense
  • NF-kappa B / genetics
  • Nuclear Proteins / biosynthesis*
  • Nuclear Proteins / genetics
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Tumor Suppressor Proteins / biosynthesis*
  • Tumor Suppressor Proteins / genetics

Substances

  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Nuclear Proteins
  • Tumor Suppressor Proteins
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3

Grants and funding

This work was supported by grants from Fellinger Krebsforschung, Land Steiermark, Hygienefond, and Jubilaeumsfond der OENB and by the START-Funding-Program of the Medical University of Graz and the city of Graz. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.