Genetics and molecular biology of chronic lymphocytic leukemia.

B cell chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by accumulation of malignant CD5+ B cells. Multiple molecular events likely contribute to malignant transformation; no single genetic abnormality or event has been shown to be responsible for development of the disease. Significant advances have recently been made towards understanding the genetic and molecular basis for the etiology and clinical course of CLL. Our current understanding is only now bringing us to the point where we can use this information in management and in developing new therapies for patients with CLL. Familial clustering of CLL cases is not uncommon and implicates a genetic basis for the development of the disease in some individuals. Potential interventions in this instance could employ strategies of gene transfer or gene therapy to correct genetic defects or strategies of chemoprevention, none of which is currently under investigation. Greater potential for therapeutic intervention rests with targeting molecular aberrations and altered gene expression in leukemia cells, for example, over expression of the anti-apoptotic proteins of the Bcl-2 family. CLL follows a variable clinical course, with some patients not needing treatment for many years and responding to therapy completely and repeatedly. Other patients have rapidly progressive disease that is refractory to currently available agents and they quickly succumb to their disease. One major recent advance has been the identification of molecular and genetic prognostic factors that can be used in early-stage patients to identify those likely to rapidly progress. This affords the opportunity to tailor management for patients based on the predictable aggressiveness of their disease. Molecular and genetic findings are increasingly influencing management decisions in CLL. Bone marrow transplantation may be considered for a patient with unfavorable prognostic features earlier than for a patient with favorable features and same clinical stage of disease. It is likely that these genetic and molecular-based factors will be targets of new treatment modalities that fundamentally change the management of this disease. In this review we detail the current understanding of the genetics and molecular biology of CLL and introduce potentials for therapeutic intervention.