It is currently well established that chronic myelogeneous leukemia (C
ML) results from the activation of multiple signalling pathways by the
Philadelphia chromosome (Phl) 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 wi
th major signalling pathways but the roles of the latter in the result
ing leukemic phenotypes are not well understood. Several major signall
ing pathways shown to be activated by BCR-ABL, including RAS, MYC, TUN
, STAT, PI-3K and NF-KB are briefly discussed in this paper. Other sig
nalling molecules are also clearly involved, including p62-DOK, p95-VA
V,CRK-L, p120-CBL and focal adhesion proteins. Recent experimental evi
dence also indicates that negative regulatory proteins could be activa
ted 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 ex
perimental systems BCR-ABL has a clear anti-apoptotic activity and tha
t BCR-ABL achieves this effect by acting upstream of the procaspase-3.