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 V_Hgene 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 immunoglobulinV_Hgene status. In CLL, V_Hgene mutational status likely does not change over the course of the disease. In the studies describing CLUS, only mutatedV_Hgene status was observed. Is this observation explained by the small patient sample size examined forV_Hgene 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 V_Hgene CLL or unmutated V_H gene CLL without a CLUS phase? Alternatively, prior to developing CLL, does a proportion of unmutated V_Hgene CLL patients develop somatic V_H 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.