Translocation t(X;11)(q13;q23) in B-cell chronic lymphocytic leukemia disrupts two novel genes

Genes Chromosomes Cancer. 2005 Feb;42(2):128-43. doi: 10.1002/gcc.20131.

Abstract

Deletion of chromosome region 11q22-q23 defines a subgroup of patients with B-cell chronic lymphocytic leukemia (B-CLL) characterized by poor survival. Although the tumor-suppressor gene ATM in the consensus deletion region was found to be biallelically inactivated in about one third of B-CLL cases, in the majority of those who have this deletion, inactivation of the remaining ATM allele was not observed. To identify a second disease-associated gene, we investigated two B-CLL cases with translocation breakpoints in the critical 11q23 deletion region. In one case, a t(X;11)(q13;q23) was cloned and two novel genes were isolated. The breakpoint on 11q23 affected the ARHGAP20 gene, which encodes a protein predicted to be involved in the regulation of Rho family GTPases. The breakpoint on Xq13 occurred in BRWD3, which codes for a putative novel transcription factor. The rearrangement of ARHGAP20 and BRWD3 did not result in fusion transcripts, but it disrupted both genes. Mutation analysis of 28 B-CLL samples with monoallelic deletions and two B-CLL samples with 11q23 translocations detected no deleterious mutation in the remaining copy of ARHGAP20. Quantitative expression analysis in 22 B-CLLs revealed significant up-regulation of ARHGAP20 in CLL B cells, whereas BRWD3 was slightly down-regulated. Thus, deregulation of ARHGAP20 by altered gene expression or by gene disruption (but not point mutation) might be a general molecular mechanism of B-CLL leukemogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosome Banding / methods
  • Chromosome Breakage / genetics
  • Chromosome Deletion
  • Chromosomes, Human, Pair 11 / genetics*
  • Chromosomes, Human, X / genetics*
  • Cloning, Molecular / methods
  • DNA Mutational Analysis / methods
  • DNA, Neoplasm / genetics
  • Exons / genetics
  • GTPase-Activating Proteins
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Molecular Sequence Data
  • Oncogene Proteins, Fusion / genetics
  • RNA Splice Sites / genetics
  • Transcription Factors / genetics*
  • Transcription Factors / physiology
  • Translocation, Genetic / genetics*

Substances

  • ARHGAP20 protein, human
  • BRWD3 protein, human
  • DNA, Neoplasm
  • GTPase-Activating Proteins
  • Oncogene Proteins, Fusion
  • RNA Splice Sites
  • Transcription Factors

Associated data

  • GENBANK/AY496263
  • GENBANK/AY496264
  • GENBANK/AY496265
  • GENBANK/AY496266
  • GENBANK/AY496267
  • GENBANK/AY497046
  • GENBANK/AY497047
  • GENBANK/AY497048
  • GENBANK/AY497049
  • GENBANK/AY497050
  • GENBANK/AY497051
  • GENBANK/AY497052
  • GENBANK/AY497053
  • GENBANK/AY497054
  • GENBANK/AY497055
  • GENBANK/AY497056
  • GENBANK/AY497057
  • GENBANK/AY497058
  • GENBANK/AY497059
  • GENBANK/AY497060