Molecular pathophysiology of chronic myelogenous leukemia

It is currently well established that chronic myelogeneous leukemia (CML) results from the activation of multiple signalling pathways by the Philadelphia chromosome (Ph1) and its molecular counterpart, the BCR-ABL oncogene. Deletion and site-directed mutagenesis experiments have determined the critical regions of the oncogene for its interaction with major signalling pathways but the roles of the latter in the resulting leukemic phenotypes are not well understood. Several major signalling pathways shown to be activated by BCR-ABL, including RAS, MYC, JUN, STAT, PI-3K and NF-KB are briefly discussed in this paper. Other signalling molecules are also clearly involved, including p62-DOK, p95-VAV, CRK-L, p12O-CBL and focal adhesion proteins. Recent experimental evidence also indicates that negative regulatory proteins could be activated in cells expressing BCR-ABL and their inhibition during the course of the disease could play a role in the progression towards the acute phase. We finally discuss the evidence indicating that at least in experimental systems BCR-ABL has a clear anti-apoptotic activity and that BCR-ABL achieves this effect by acting upstream of the procaspase-3.