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Blood, Vol. 95 No. 11 (June 1), 2000:
pp. 3534-3540
Somatic mutation of bcl-6 genes can occur in the absence
of VH mutations in chronic lymphocytic leukemia
Surinder S. Sahota,
Zadie Davis,
Terry J. Hamblin, and
Freda K. Stevenson
From the Molecular Immunology Group, Tenovus Laboratory, Southampton
University Hospitals, Southampton, UK.
Somatic mutation in immunoglobulin variable (V) region genes occurs
largely in the germinal center and, after neoplastic transformation, imprints V genes of B-cell tumors with the mutational history of the
cell of origin. Recently, it has been found that chronic lymphocytic
leukemia (CLL) consists of 2 subsets, each with a different clinical
course, one with unmutated VH genes consistent with a naive
B cell, and the other with mutated VH genes consistent with
transit through the germinal center. However, somatic mutation also
occurs at another distinct locus, the 5' noncoding region of the
bcl-6 gene, in both B-cell tumors and in normal germinal center
B cells. To probe the suggestive link between the occurrence of
mutations in VH and bcl-6 genes, we analyzed the
nature of somatic mutation at these distinct loci in the 2 CLL subsets. Unexpectedly, we found no such link in the CLLs defined by unmutated VH genes, with 4 of 10 cases clearly showing mutations in
bcl-6. In those CLLs defined by somatically mutated
VH genes, 4 of 9 cases predictively showed bcl-6
mutations. The frequency of bcl-6 mutations was comparable in
both subsets, with mutations being biallelic, and in 3 of 8 cases
indicative of clonal origins. Surprisingly, intraclonal variation,
which is not a feature of VH genes in CLL, was found in 6 of 8 cases in both subsets. These data indicate that somatic mutation
of the VH and bcl-6 loci may not necessarily occur
in tandem in CLL, suggesting diverse pathways operating on the 2 genes.
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