Prevalent involvement of illegitimate V(D)J recombination in chromosome 9p21 deletions in lymphoid leukemia

J Biol Chem. 2002 Nov 29;277(48):46289-97. doi: 10.1074/jbc.M208353200. Epub 2002 Sep 12.

Abstract

To understand molecular pathways underlying 9p21 deletions, which lead to inactivation of the p16/CDKN2A, p14/ARF, and/or p15/CDKN2B genes, in lymphoid leukemia, 30 breakpoints were cloned from 15 lymphoid leukemia cell lines. Seventeen (57%) breakpoints were mapped at five breakpoint cluster sites, BCS-LL1 to LL5, each of <15 bp. Two breakpoint cluster sites were located within the ARF and CDKN2B loci, respectively, whereas the remaining three were located >100 kb distal to the CDKN2A, ARF, and CDKN2B loci. The sequences of breakpoint junctions indicated that deletions in the 11 (73%) cell lines were mediated by illegitimate V(D)J recombination targeted at the five BCS-LL and six other sites, which contain sequences similar to recombination signal sequences for V(D)J recombination. An extrachromosomal V(D)J recombination assay indicated that BCS-LL3, at which the largest number of breakpoints (i.e. five breakpoints) was clustered, has a V(D)J recombination potential 150-fold less than the consensus recombination signal sequence. Three other BCS-LLs tested also showed V(D)J recombination potential, although it was lower than that of BCS-LL3. These results indicated that illegitimate V(D)J recombination, which was targeted at several ectopic recombination signal sequences widely distributed in 9p21, caused a large fraction of 9p21 deletions in lymphoid leukemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Chromosome Deletion*
  • Chromosomes, Human, Pair 9*
  • Cloning, Molecular
  • DNA Nucleotidyltransferases / genetics*
  • DNA Primers
  • DNA, Neoplasm
  • Humans
  • Leukemia, Lymphoid / genetics*
  • Recombination, Genetic*
  • Sequence Homology, Amino Acid
  • Tumor Cells, Cultured
  • VDJ Recombinases

Substances

  • DNA Primers
  • DNA, Neoplasm
  • DNA Nucleotidyltransferases
  • VDJ Recombinases