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Myeloma VL and VH gene sequences reveal a complementary imprint of antigen
selection in tumor cells
SS Sahota, R Leo, TJ Hamblin and FK Stevenson
Molecular Immunology Group, Tenovus Laboratory, Southampton University
Hospitals, UK.
In multiple myeloma, sequence studies of VH genes used to encode clonal Ig
in neoplastic plasma cells have shown a common pattern of extensive somatic
hypermutation. A further consistent feature of these VH sequences is a
complete lack of intraclonal variation. These findings indicate that the
malignant cell arises at a mature, postfollicular stage of B-cell
development. However, only a minority of cases have a distribution of
somatic mutations in VH consistent with a prior role for antigen in
selecting the B cell of origin. To complement these studies, and to take
further the investigation of a role for antigen in the clonal history of
myeloma, we have investigated tumor-derived VL sequences from bone marrows
of 15 patients. All sequences (9V kappa and 6V lambda A) were potentially
functional and 5 of 15 had evidence for N- region additions. All had
undergone extensive somatic hypermutation, and showed no intraclonal
variation. In 4 of 15 cases, the distribution of mutations revealed a
significant (P < .05) clustering of replacement mutations in the CDR
sequences, indicating a role for VL in selection by antigen. Comparison
with the VH sequences used by the same tumor cells showed that, if
significant clustering was present, it was in either VH or VL but not both.
Altogether, 10 of 15 V-regions showed evidence for antigen selection,
suggesting that the B cell of origin has behaved as a normal germinal
center B cell. Deductions concerning a role for antigen selection may
require both VH and VL sequences for validation.
Volume 89,
Issue 1,
pp. 219-226,
01/01/1997
Copyright © 1997 by The American Society of Hematology
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