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Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1413-1419
Analysis of expressed immunoglobulin heavy chain genes in familial
B-CLL
Akira Sakai,
Gerald E. Marti,
Neil Caporaso,
Stefania Pittaluga,
Jeffrey W. Touchman,
Falko Fend, and
Mark Raffeld
From the Hematopathology Section, Laboratory of Pathology, National
Cancer Institute, National Institute of Health, and Flow and Image
Cytometry Section, Laboratory of Medical and Molecular Genetics,
Division of Cell and Gene Therapies, Center for Biologics Research and
Evaluation, Food and Drug Administration, Bethesda; Genetic
Epidemiology Branch, National Cancer Institute, National Institute of
Health, Rockville; and NIH Intramural Sequencing Center and National
Human Genome Research Institute, National Institute of Health,
Gaithersburg, MD.
In this study, we wished to determine whether familial chronic
lymphocytic leukemia of B-cell phenotype (CLL) shares with sporadic
B-CLL the same immunoglobulin (Ig) heavy chain variable region (VH)
gene usage and occurrence of somatic mutation, to gain insight into the
pathogenetic relatedness of these epidemiologically distinct forms of
CLL. We therefore analyzed the expressed Ig heavy chain genes in 23 cases (11 families) of familial CLL, and compared these results with
data previously reported for sporadic CLL. In addition, we assessed the
relationship of the occurrence of somatic mutation to several clinical
and phenotypic features. The distribution of V genes among these cases
was similar to that observed in sporadic CLL: VH3 > VH1 > VH4.
Thirteen of the 23 cases (57%) showed germ line VH gene sequences,
whereas somatic mutations were detected in 10 cases (43%). The average
mutation frequency of these latter 10 cases of was 6.7% (ranging from
1.7% to 8.8%), and evidence of antigen selection was noted in 6. Intraclonal variation, followed by clonal evolution and the appearance
of a second clone over a 20-year period was observed in 1 case,
suggesting that mutations can continue to accumulate after neoplastic
transformation. The presence of somatic mutations correlated with age
at presentation, low white blood cell (WBC) count, and low fluorescence
intensity of surface CD5, and the potential significance of these
relationships is discussed. Our data indicate that familial and
sporadic B-CLL display a similar pattern of immunoglobulin gene usage
and frequency of somatic mutation, and are consistent with a common
ontogeny and immunogenetic origin for these 2 epidemiologically
distinct forms of CLL.
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