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Templated Nucleotide Addition and Immunoglobulin J_H-Gene Utilization in t(11;14) Junctions: Implications for the Mechanism of Translocation and the Origin of Mantle Cell Lymphoma¹

Department of Internal Medicine I, Division of Hematology [N. W., T. L., R. M., K. L., B. N., U. J.], Department of Internal Medicine I, Division of Oncology [J. D., M. R.], Department of Clinical Chemistry and Laboratory Medicine [G. M., C. M.], and Department of Pathology [A. C.], University of Vienna, A-1090 Vienna, Austria; Department of Medicine II, University of Kiel, 24116 Kiel, Germany [C. P., M. K.]; Department of Histopathology, Royal Free and University College London Medical School, WC1E 6JJ London, United Kingdom [M-Q. D.]; and Department of Molecular Medicine, Ruder Boskovic Institute, HR-10000 Zagreb, Croatia [R. K.]

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_H6 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 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.

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