Leukemogenesis and new therapy development: the example of chronic myelogenous leukemia

During the past ten years, the improvements of our understanding of cellula r signal transduction pathways provide new targets for drug therapies. Chro nic myeloid leukemia (CML), a malignant hematopoietic stem cell disorder, i s characterised by an acquired genetic abnormality: the Philadelphia chromo some (Ph) and its molecular counterpart, the oncogene BCR-ABL. The latter, which is translated in an active BCR-ABL protein, exhibited a deregulated t yrosine kinase activity inducing malignant transformation. Produced from th e 2-phenylaminopyrimidine class, a novel synthetic inhibitor, identified as CGP57148 (STI571), inhibits tyrosine kinase activity of c-ABL, BCR-ABL, PD GF-R and c-kit at micromolar concentrations. It suppresses the proliferatio n of the majority of BCR-ABL positive cell lines. The phases I-II clinical trials in CML have demonstrated promising results, especially in the chroni c phase of the disease. STI571 is an original therapeutic approach which ma y be used as a model for the development of other drugs in cancer.