Molecular pathogenesis

Chronic lymphocytic leukemia (CLL) is a common hematologic malignancy with high prevalence in the West (1). In the 1990 decade, the incidence of CLL in the United States equals to 5.17 per 100,000 person-years, only surpassed by incidence of diffuse large B-cell lymphoma and multiple myeloma (2). The vast majority of CLL is B-CLL. CLL B cells are mature CD5+/CD19+/CD23+ B lymphocytes that express low levels of surface immunoglobulins (Ig) such as IgM or IgD (3). Some patients die from the disease within a few months of the diagnosis, whereas others live for 20 years or more (4). The clinical staging systems devised by Rai et al. (5) and Binet et al. (6) are useful methods to identify patients with short survival. However, these staging systems cannot be used to predict the individual risk of disease progression and survival in the early stages of CLL (Binet stage A or Rai stage 0 to 2 disease) in most patients. Conventional cytogenetics is of limited clinical value because of the low mitotic activity of the leukemic cells, which are nondividing G0 cells (7). Recent advances in the molecular dissection of CLL proved that the molecular pathogenesis of this disease is very complicated and further proved the basis of a new dogma in molecular biology (for extensive reviews on these topics see Refs. 8-10) (Fig. 1, Table 1). Further strengthening the importance of the genetic component in CLL, a high level of familial aggregation was described in this disease (11).