engleski

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 immunogobulin heavy chain gene (IgH) loci in mantle cell lymphoma (MCL) is 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). Reasoning that the earlier (pre-germinal 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 with MCL. Thirty-six samples (39%) were positive for the direct (BCL-1/JH) and 23 for both direct and reciprocal (DH/BCL-1) junctions. The breaks on chromosome 14 exhibited features of V(D)J-mediated recombination as shown by DH and JH 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 mechansim of cleavage. The use of JH6 in the junctions (39%) was similar to that in the Ig genes of normal B-cells and B-CLL, but considerably less than in FL. Only 2 of 36 samples contained a BCL-1/DJH rearrangement indicative of a previous DJH rearrangement. Most importantly, 19% of the BCL-1/IgH junctions with inserts more than 4 nucleotides contained error-prone copies (T-nucleotides) of 8-12 nt 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 Ig genes. We concluded 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 JH regions suggest that the t(11;14) occurs predominantly during an attempted primary DH-JH rearrangement in early B-cells, while the t(14;18) mostly occurs during secondary rearrangement. This is in agreement with the pre-germinal center B-cell origin of MCL.

Mantle cell lymphoma; templated oligonucloetides; translocation

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