Introduction

CLL is a disease of a subtype of mature B cells characterized by expression of a specific combination of cell surface molecules: CD5+, CD19+, CD23+; surface immunoglobulin (sIg) and CD20 are expressed at only low levels. Histologically, the disease is rather bland, and usually, should present little problem in diagnosing. However, despite the morphological homogeneity, the disease varies enormously in prognosis, with some patients requiring no treatment for many years, if ever, while others die rapidly with chemotherapy-resistant disease.

In the basic biology of CLL, considerable progress has been made. The paradigm of CLL we have lived with for the past 40 years, that CLL is a disease of immunologically inert mature B cells, arising due to suppressed apoptosis, is being increasingly challenged. In the peripheral blood, viability of CLL cells appears to be dependent on intercellular contact with specialized subsets of dendritic or "nurse-like" cells, while other cell types may fulfil comparable roles in other sites.12 In vivo metabolic labeling with heavy water suggests an unexpectedly high turnover of cells3 (see also www.kinemed.com). Studies on the sequences of the expressed immunoglobulin (IG) variable region (IGHV) gene sequences are shedding new light on the possible pathogenesis of this disease. Furthermore, a subclinical expansion of CLL cells has been described, which appears to be the equivalent of monoclonal gammopathy of undetermined significance (MGUS).4 Within molecular cytogenetics analysis, progress has been hampered by the lack of a consistent cytogenetic lesion. The most common abnormality, involving deletion of a small region of chromosome 13q14, may involve loss of expression of micro RNA gene expression.5 Clinically, molecular genetic analysis of the tumor cells, not only by molecular cytogenetics but also by mutational analysis of IGHV sequences, are now mandatory components for diagnosis in CLL and will eventually predict therapy.6 Notably, patients with mutated IGHV have a much better prognosis than those with germline segments.7 Similarly, patients with deletions and mutations involving either the p53 gene on chromosome 17p13.3 or the ATM gene on 11q23.1 fare badly.8 Determining the nature of the molecular events associated with these different subgroups is now a major challenge.

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