Prevalent involvement of illegitimate V(D)J recombination in chromosome 9p21 deletions in lymphoid leukemia.
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.
Kitagawa
Yukiko
Y
Biology Division, National Cancer Center Research Institute, Tokyo 1040045, Japan.
Inoue
Kaoru
K
Sasaki
Shigeru
S
Hayashi
Yasuhide
Y
Matsuo
Yoshinobu
Y
Lieber
Michael R
MR
Mizoguchi
Hideaki
H
Yokota
Jun
J
Kohno
Takashi
T
D001483:Base Sequence; D002872:Chromosome Deletion; D002899:Chromosomes, Human, Pair 9; D003001:Cloning, Molecular; D004254:DNA Nucleotidyltransferases / Q000235:genetics*; D017931:DNA Primers; D004273:DNA, Neoplasm; D006801:Humans; D007945:Leukemia, Lymphoid / Q000235:genetics*; D011995:Recombination, Genetic; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured; D045567:VDJ Recombinases
D017931:DNA Primers; D004273:DNA, Neoplasm; D004254:DNA Nucleotidyltransferases; D045567:VDJ Recombinases