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Molecular characterization of IgA- and/or IgG-switched chronic lymphocytic
leukemia B cells
A Matolcsy, P Casali, RG Nador, YF Liu and DM Knowles
Department of Pathology, University Medical School of Pecs, Hungary.
The immunoglobulin (Ig) variable region (V) genes expressed by IgM chronic
lymphocytic leukemia (CLL) B cells display little or no somatic mutations.
However, preliminary findings have shown that Ig V genes of IgA and IgG
CLLs may be somatically mutated, suggesting that isotype- switched CLLs may
represent a "subtype" of the disease. To investigate the degree and nature
of somatic mutations and the role of antigen (Ag) in the clonal selection
and expansion of isotype-switched CLLs, and to determine whether specific
oncogene or tumor suppressor gene mutations are associated with
isotype-switched CLLs, we analyzed the expressed Ig VH gene, bcl-1 and
bcl-2 proto-oncogene, and p53 tumor suppressor gene configurations of 3
IgA-, 1 IgG-, and 1 IgA/ IgG-expressing CLLs. These isotype-switched CLL B
cells expressed surface HLA-DR, CD19, CD23, and CD5, and displayed no
alterations of the bcl-1 and bcl-2 oncogenes and the p53 tumor-suppressor
gene. The cDNA VH-D-JH gene sequence was joined with that of the C alpha
gene in the B cells of the three IgA CLLs, and with that of the C gamma
gene in the IgG CLL B cells. In the IgA/IgG-coexpressing CLL B cells,
identical VH-D-JH cDNA sequences were spliced to either C alpha or C gamma
genes. In all five CLLs, the pattern of C mu DNA probe hybridization to the
digested genomic DNAs was consistent with deletion of the C mu exon from
the rearranged Ig gene locus, suggesting that these CLL B cells had
undergone DNA switch recombination. In one IgA CLL, the expressed VH gene
was unmutated. In all other class-switched CLLs, the Ig VH segment gene was
mutated, but the point mutations were not associated with intraclonal
diversification. In one IgA and in the IgA/IgG-coexpressing CLL, the nature
and distribution of the mutations were consistent with Ag selection. These
findings suggest that IgA- and/or IgG-expressing CLLs represent, in their
VH gene structure, transformants of B cells at different stages of
ontogeny. They also suggest that Ag may play a role in the clonal selection
of some of these isotype-switched leukemic cells, but bcl-1 and bcl-2
oncogene rearrangements and p53 tumor suppressor gene mutation are not
associated with the pathogenesis of isotype-switched CLLs.
Volume 89,
Issue 5,
pp. 1732-1739,
03/01/1997
Copyright © 1997 by The American Society of Hematology
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