Templated nucleotide addition and immunoglobulin JH-gene utilization in t(11;14) junctions: implications for the mechanism of translocation and the origin of mantle cell lymphoma.
The t(11;14)(q13;q32) between the BCL-1 and immunoglobulin heavy chain gene (IgH) loci in mantle cell lymphoma (MCL) are believed to be mediated by the mechanism of V(D)J recombination similar to the t(14; 18) in follicular lymphoma (FL). We have recently shown that the t(14;18) event creates staggered double-strand breaks in the BCL-2 locus, and that the t(14;18) junctions contain templated nucleotide insertions (T-nucleotides; U. Jäger et al., Blood, 95: 3520-3529, 2000). Reasoning that the earlier (pregerminal center) B-cell origin of MCL might be reflected in a different molecular structure of the chromosomal breakpoints, we PCR-amplified diagnostic samples from 93 patients. Thirty-six samples (39%) were positive for the direct (BCL-1/J(H)) and 23 for both direct and reciprocal (D(H)/BCL-1) junctions. The breaks on chromosome 14 exhibited features of V(D)J-mediated recombination as shown by D(H) and J(H) coding end processing. However, duplications of BCL-1 sequences in 39% of the 23 patients indicate staggered double-strand breaks in the major translocation cluster region (MTC). This is incompatible with V(D)J recombination and indicates a different mechanism of cleavage. The use of J(H)6 in the junctions (39%) was similar to that in the immunoglobulin genes of normal B cells and B-CLL, but considerably less than in FL. Only 2 of 36 samples contained a BCL-1/DJ(H) rearrangement, which was indicative of a previous DJ(H) rearrangement. Most importantly, 19% of the BCL-1/IgH junctions with inserts of > or =5 nucleotides contained error-prone copies (T-nucleotides) of 8-12 nucleotides originating from the surrounding BCL-1 or IgH regions, a lower rate than in FL. No correlation was found between the addition of T-nucleotides and the rate of somatic mutation in the immunoglobulin genes. We conclude that the t(11;14) and t(14;18) use the same basic mechanism of translocation including V(D)J-mediated recombination, double-strand staggered breaks, and template-dependent, error-prone DNA-synthesis. However, the distinct differences in the utilization of J(H) regions suggest that the t(11;14) occurs predominantly during an attempted primary D(H)-J(H) rearrangement in early B cells, whereas the t(14;18) mostly occurs during secondary rearrangement. This is in agreement with the pregerminal center B-cell origin of MCL.
Department of Internal Medicine, University of Vienna, Austria.
N
N
Welzel
T
T
Le
R
R
Marculescu
G
G
Mitterbauer
A
A
Chott
C
C
Pott
M
M
Kneba
M Q
MQ
Du
R
R
Kusec
J
J
Drach
M
M
Raderer
C
C
Mannhalter
K
K
Lechner
B
B
Nadel
U
U
Jaeger
D001483:Base Sequence; D019457:Chromosome Breakage / Q000235:genetics; D002880:Chromosomes, Human, Pair 11; D002883:Chromosomes, Human, Pair 14; D004251:DNA Transposable Elements / Q000235:genetics; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000235:genetics; D005803:Genes, Immunoglobulin / Q000235:genetics*; D019940:Genes, bcl-1 / Q000235:genetics; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007130:Immunoglobulin Idiotypes / Q000235:genetics; D007144:Immunoglobulin J-Chains / Q000235:genetics*; D020522:Lymphoma, Mantle-Cell / Q000235:genetics*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D013698:Templates, Genetic; D014178:Translocation, Genetic / Q000235:genetics*
D004251:DNA Transposable Elements; D007143:Immunoglobulin Heavy Chains; D007130:Immunoglobulin Idiotypes; D007144:Immunoglobulin J-Chains