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Blood, Vol. 95 No. 11 (June 1), 2000:
pp. 3520-3529
Follicular lymphomas' BCL-2/IgH junctions contain templated
nucleotide insertions: novel insights into the mechanism of t(14;18)
translocation
Ulrich Jäger,
Silke Böcskör,
Trang Le,
Gerlinde Mitterbauer,
Ingrid Bolz,
Andreas Chott,
Michael Kneba,
Christine Mannhalter, and
Bertrand Nadel
From the Department of Internal Medicine I, Division of Hematology,
Department of Clinical Chemistry and Laboratory Medicine, and
Department of Pathology, University of Vienna, Vienna, Austria; and the
Department of Medicine II, University of Kiel, Kiel, Germany.
The human t(14;18) chromosomal translocation is assumed to result
from illegitimate rearrangement between BCL-2 and
DH/JH 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/JH) and reciprocal (DH/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, DH,
and JH 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 t(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 DH to JH rearrangement, and
an additional unidentified mechanism creating the initial breaks on
chromosome 18. Altogether, these data suggest that the t(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.
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