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Blood, 1 September 2000, Vol. 96, No. 5, pp. 1947-1952
NEOPLASIA
V(D)J recombinase-mediated transposition of the BCL2
gene to the IGH locus in follicular lymphoma
Jan-Willem Vaandrager,
Ed Schuuring,
Katja Philippo, and
Philip M. Kluin
From the Department of Pathology, Leiden University
Medical Center, Leiden, The Netherlands.
Using DNA fiber fluorescence in-situ hybridization
(FISH) and 3-color interphase FISH, 2 cases of follicular lymphoma were identified in which the BCL2 gene was excised from 18q21
and inserted into the immunoglobulin heavy chain (IGH)
locus at 14q32. Both the insertion breakpoint at 14q32 and the deletion
breakpoint at 18q21 were cloned using inverse polymerase chain
reaction. Sequence analysis showed that the JH sequences were
juxtaposed to the 5'-side of BCL2, and the DH sequences
were juxtaposed to the 3'-side of BCL2. There were
breakpoints at both the JH and DH recombination signal sequences, and
N-nucleotides were present at all breakpoint junctions. At the
BCL2 locus, the 3'-breakpoints in both cases were localized
at exactly the same nucleotide position, 6.2 kilobase downstream
of the major breakpoint region, directly adjacent to a complete cryptic
recombination signal sequence (RSS) consisting of a heptamer, a
nonamer, and a 23-base pair (bp) spacer. The BCL2
5'-breakpoints were approximately 600 bp upstream of the gene,
within the CA repeats. Although less evident than for the BCL2
3'-breakpoints, cryptic RSSs were also identified at these
breakpoints, with a 12-bp spacer. On the basis of structural characteristics of these rearrangements, a model is proposed in which
the BCL2 gene is deleted from its locus by recombination activation gene-1/-2 (RAG-1/-2)-mediated excision. The
gene is subsequently inserted into the recombining
IGH locus, a process involving the formation of hybrid
joints between the IGH coding ends and the
BCL2 signal ends.
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