Blood, 1 October 2002, Vol. 100, No. 7, pp. 2277-2277
Clonal lymphocytosis of uncertain significance (CLUS): what
clues will CLUS yield?
Chronic lymphocytic leukemia (CLL) is the most common adult
leukemia, yet our understanding of the molecular features associated with malignant transformation is limited. Two separate studies have
made sentinel observations documenting the presence of a clonal
lymphocytosis of uncertain significance (CLUS) in healthy volunteers
with normal lymphocyte counts. Although infrequent in number, these
CLUS lymphocytes have immunophenotypic and gene-rearrangement studies
identical to those seen in patients with CLL. The first study of a
small proportion of both healthy adult volunteers (Rawstron et al,
Blood. 2002;100:635-639) demonstrates an overall 3.5% frequency that
increases with ascending age. When examined in a small number of
patients, these transformed lymphocytes had favorable mutated immunoglobulin VH gene status. Now
Rawstron and colleagues (page 2289) describe a higher frequency of CLUS
(13.5%) among first-degree relatives of patients with CLL than
among healthy volunteers. The increased frequency of CLUS will allow
for genetic linkage studies in larger numbers of affected patients who
do not yet manifest signs or symptoms of the disease. This potentially
will assist in identifying genes that contribute to the risk of
developing CLL.
While it will be important for other groups to reproduce these data,
several questions are raised by this sentinel description of CLUS.
Genomic profiling studies have suggested that CLL has one disease-
specific gene profile that can be further categorized based upon the
presence or absence of mutated or unmutated immunoglobulin VH gene status. In CLL, VH
gene mutational status likely does not change over the course of
the disease. In the studies describing CLUS, only mutated
VH gene status was observed. Is this observation explained by the small patient sample size examined for
VH gene status, or does it suggest a common CLL
progenitor cell with a divergent malignant transformation process that
can produce either CLUS followed rarely by mutated VH
gene CLL or unmutated VH gene CLL without a
CLUS phase? Alternatively, prior to developing CLL, does a proportion
of unmutated VH gene CLL patients develop
somatic VH gene mutation and proceed onto a
benign CLUS course? Finally, is it possible that CLL represents 2 distinct B-cell malignancies? As with most novel reports of this
magnitude, many more questions arise than are answered.
At the practical level, for the clinician it will be very
important to determine the clinical significance of CLUS and to serially characterize molecular features associated with clinical progression to CLL when this occurs. Just as the recognition and long-term follow-up studies of monoclonal gammopathy of uncertain significance has yielded an enormous amount of information about the pathogenesis of multiple myeloma, it is hoped that
careful prospective studies of CLUS within both the general population and those families affected by familial CLL will improve our
understanding of this common adult leukemia.
John C. Byrd
The Ohio State
University
