Analysis of 11q22-q23 deletion target genes in B-cell chronic lymphocytic leukaemia: evidence for a pathogenic role of NPAT, CUL5, and PPP2R1B

Eur J Cancer. 2007 May;43(8):1328-35. doi: 10.1016/j.ejca.2007.02.005. Epub 2007 Apr 20.

Abstract

Deletion of 11q22-q23 is associated with an aggressive course of B-cell chronic lymphocytic leukaemia (B-CLL). Since only in a subset of these cases biallelic inactivation of ATM was observed, we sought to identify other disease-associated genes within 11q22-q23 by analysing NPAT (cell-cycle regulation), CUL5 (ubiquitin-dependent apoptosis regulation) and PPP2R1B (component of the cell-cycle and apoptosis regulating PP2A) for point mutations and their expression in B-CLL by single-strand conformation polymorphism/sequence analysis of the transcripts and real-time polymerase chain reaction. Though none of the genes were affected by deleterious mutations, we observed a significant down-regulation of NPAT in B-CLL versus CD19+ B cells and of CUL5 in 11q deletion versus non-deletion B-CLL samples and measured reduced PPP2R1B transcript levels in a subset of B-CLL cases. Alternative splicing of PPP2R1B transcripts (skipping of exons 2/3, 3, 9) was associated with a reduced activity of protein phosphatase 2A. Together, these results implicate deregulation of the cell-cycle and apoptosis regulators NPAT, CUL5 and PPP2R1B and a role for these genes in the pathogenesis of B-CLL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence / genetics
  • Cell Cycle Proteins / genetics*
  • Chromosome Deletion*
  • Chromosomes, Human, Pair 11 / genetics*
  • Cullin Proteins / genetics*
  • DNA Mutational Analysis
  • Down-Regulation
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Mutation / genetics
  • Neoplasm Proteins / genetics*
  • Nuclear Proteins / genetics*
  • Polymerase Chain Reaction / methods
  • Protein Phosphatase 2
  • Reverse Transcriptase Polymerase Chain Reaction / methods

Substances

  • CUL5 protein, human
  • Cell Cycle Proteins
  • Cullin Proteins
  • NPAT protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • PPP2R1B protein, human
  • Protein Phosphatase 2