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Blood, Vol. 94 No. 6 (September 15), 1999:
pp. 1848-1854
Unmutated Ig VH Genes Are Associated With a More
Aggressive Form of Chronic Lymphocytic Leukemia
Terry J. Hamblin,
Zadie Davis,
Anne Gardiner,
David G. Oscier, and
Freda K. Stevenson
From the Department of Haematology, Royal Bournemouth Hospital,
Bournemouth, UK; and the Molecular Immunology Department, Tenovus
Research Laboratory, Southampton General Hospital, Southampton,
UK.
Despite having several characteristics of naïve B cells,
chronic lymphocytic leukemia (CLL) cells have been shown in some cases
to have somatically mutated Ig variable region genes, indicating that
the cell of origin has passed through the germinal center. A previous
study of patients with CLL found an association between lack of somatic
mutation and trisomy 12 and, therefore, possibly with a less favorable
prognosis. We have sequenced the Ig VH genes of the tumor
cells of 84 patients with CLL and correlated our findings with clinical
features. A total of 38 cases (45.2%) showed  98% sequence
homology with the nearest germline VH gene; 46 cases
(54.8%) showed >2% somatic mutation. Unmutated VH genes were significantly associated with V1-69 and D3-3 usage, with atypical
morphology; isolated trisomy 12, advanced stage and progressive disease. Survival was significantly worse for patients with unmutated VH genes irrespective of stage. Median survival for stage A
patients with unmutated VH genes was 95 months compared
with 293 months for patients whose tumors had mutated VH
genes (P = .0008). The simplest explanation is that
CLL comprises 2 different diseases with different clinical courses.
One, arising from a memory B cell, has a benign course, the other,
arising from a naïve B cell, is more malignant.
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