Follicular lymphomas' BCL-2/IgH junctions contain templated nucleotide insertions:: novel insights into the mechanism of t(14;18) translocation

The human t(14;18) chromosomal translocation is assumed to result from illegitimate rearrangement between BCL-2 and D-H/J(H) gene segments during V(D)J recombination In early B cells. De novo nucleotides are found inserted in most breakpoints and have been thus far interpreted as nontemplated N region additions. In this report, we have analyzed both direct (BCL-2/J(H)) and reciprocal (D-H/BCL-2) breakpoints derived from 40 patients with follicular lymphoma with t(14;18), Surprisingly, we found that more than 30% of the breakpoint junctions contain a novel type of templated nucleotide insertions, consisting of short copies of the surrounding BCL-2, D-H, and J(H) sequences. The features of these templated nucleotides, including multiplicity of copies for 1 template and the occurrence of mismatches in the copies, suggest the presence of a short-patch DNA synthesis, templated and error-prone. In addition, our analysis clearly shows that 1(14;18) occurs during a very restricted window of B-cell differentiation and involves 2 distinct mechanisms: V(D)J recombination, mediating the breaks on chromosome 14 during an attempted secondary D-H to J(H) rearrangement, and an additional unidentified mechanism creating the initial breaks on chromosome 18. Altogether, these data suggest that the 1(14;18) translocation is a more complex process than previously thought, involving the interaction and/or subversion of V(D)J recombination with multiple enzymatic machineries. (Blood. 2000;95:3520-3529) (C) 2000 by The American Society of Hematology.