Templated nucleotide addition and immunoglobulin J(H)-gene utilization in t(11;14) junctions: Implications for the mechanism of translocation and theorigin 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 th e mechanism of V(D)J recombination similar to the t(14; 18) in follicular l ymphoma (FL), We have recently shown that the t(14;18) event creates stagge red double-strand breaks in the BCL-2 locus, and that the t(14;18) junction s contain templated nucleotide insertions (T-nucleotides; U. Jager et at, B lood, 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 9 3 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 sho wn by D-H and J(H) coding end processing. However, duplications of BCL-1 se quences in 39% of the 23 patients indicate staggered double-strand breaks i n 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 j unctions with inserts of greater than or equal to5 nucleotides contained er ror-prone copies (T-nucleotides) of 8-12 nucleotides originating from the s urrounding BCL-1 or IgH regions, a lower rate than in FL. No correlation wa s found between the addition of T-nucleotides and the rate of somatic mutat ion 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 rec ombination, double-strand staggered breaks, and template-dependent, error-p rone DNA-synthesis, However, the distinct differences in the utilization of J(H) regions suggest that the t(11;14) occurs predominantly during an atte mpted 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 th e pregerminal center B-cell origin of MCL.