BCR-ABL and Human Cancer

The BCR-ABL oncogene was the first chromosomal abnormality shown to be associated with a specific human malignancy, the chronic myelogenous leukemia (CML), resulting from a reciprocal t(9;22) translocation characterized by the formation of a shortened chromosome, named Philadelphia chromosome (Ph), in which the tyrosine kinase of c-ABL is constitutively activated. This chromosomal translocation generates BCR-ABL fusion genes which can be translated in three different oncoproteins, p210, p190, and p230, associated with three different pathologies in humans, CML, acute lymphoblastic leukemia (ALL), and chronic neutrophilic leukemia, respectively. The molecular mechanisms and downstream pathways of BCR-ABL are poorly understood mainly as a result of the lack of a good in vivo model that mimics the human disease. Nevertheless, additional in vitro and in vivo models have led to the design of several novel therapeutic approaches. That is the case of Imatinib mesylate (Gleevec, STI571; Novartis Pharma AG), a drug targeting the tyrosine kinase activity of BCR-ABL and an effective therapy for chronic phase CML but not advanced stages of CML and patients with Ph ALL. The resistance mutations in the kinase domain of BCR-ABL together with the stem cell origin of the chromosomal translocation and the inability of the imatinib to inhibit the BCR-ABL activity in these cells have revealed the limitations of Gleevec, providing new lessons for the development of alternative therapies in oncology.