Dissecting the natural history of chronic lymphocytic leukemia to discover new therapeutic targets

Chronic lymphocytic leukemia (CLL), the most frequent leukemia in the western world, cannot be cured with current treatment strategies. The central clinical problem of CLL is to define which patients should be treated, when and how. Dissecting the natural history of the disease may identify disease mechanisms which may prove to be of prognostic value or lead to define molecules of potential interest as treatment targets. The rationale of this approach is demonstrated by the observation that the analysis of the mutational status of the Variable genes of the Immunoglobulin (Ig) heavy chains (IgVH) has changed dramatically our perspective of CLL. IgVH gene analysis has shown that CLL consists of at least two disease subsets which can be distinguished by the incidence of somatic mutations in the IgVH genes. Importantly the prognosis of patients in the two subsets is markedly different, with those bearing unmutated VH genes being definitely worse.