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*
Division of Molecular Immunology, Department of Pathology, Cornell University Medical College, and The Immunology Program, Cornell University Graduate School of Medical Sciences, New York, NY 10021; and
Department of Medicine, North Shore University Hospital and New York University School of Medicine, Manhasset, NY 11030
To analyze the modalities of clonal expansion of chronic
lymphocytic leukemia (CLL) cells, we sequenced at multiple time points
the V(D)J genes expressed by CD5+IgM+CLL
B cells in three patients. All three V(D)J gene sequences were found to
be point mutated. The mutation frequency in the Ig VH
(3.96 x 10-2 and 2.41 x 10-2
change/bp) and V
and V
(6.67 x 10-2 and
1.74 x 10-2 change/bp) genes of two CLLs (1.19 and
1.32, respectively) was similar, and higher than that in the
corresponding gene segments of the third CLL (1.69; 3.4 x
10-3 and 6.67 x 10-3 change/bp). In all
three CLLs, there was no preferential representation of nucleotide
changes yielding amino acid replacement (R mutations), nor was there
any preferential segregation of R mutations within the Ig V gene
complementarity-determining regions. In all three CLLs, the somatic
mutations were all identical in multiple Ig
VHDJH transcripts at any given time point, and
were all conserved at multiple time points throughout a 2-yr period.
The lack of concentration of R mutations in the
complementarity-determining regions and the lack of intraclonal
heterogeneity suggest that Ag may no longer be able to play a
significant role in the clonal expansion of these cells. This
conclusion would be strengthened further by the germline configuration
of the bcl-1 and bcl-2 proto-oncogenes that are
translocated in neoplastic B cells that display significant traces of
intraclonal diversification and Ag-dependent selection, such as
B-prolymphocytic leukemia and low grade follicular non-Hodgkin
lymphoma.
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