Molecular deregulations mediated by Bcr-Abl in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative disorder resulting in an accumulation of myeloid cells and their progenitors. CML is the result of a reciprocal translocation between the long arms of chromosomes 9 and 22. The c-ABL proto-oncogene (chromosome 9) is translocated to the major breakpoint cluster region within the BCR gene on chromosome 22 (Philadelphia chromosome or Ph). The BCR-ABL fusion gene encodes a 210 kDa protein with enhanced tyrosine kinase activity. In vitro and in vivo experiments show evidences fora causal relationship between the BCR-ABL oncogene and leukemia. The normal Bcr protein may be at the intersection of signal transduction pathways and Abl kinase is known to have a function in the regulation of cell growth. Several substrates of Bcr-Abl have been identified, including Shc, Ras-GAP, Syp, Fes, Vav, Crkl, Bap-1... The mechanisms leading to the expansion of cells expressing the chimeric protein are not completely understood. However some consistent and well studied models call be described. Bcr-Abl is involved in the stimulation of p21(ras) through the Grb-2-Sos complex. The Pas proteins in their active state have a major importance in the oncogenic potential of Bcr-Abl. The oncoprotein abrogates the anchorage requirement between myeloid cells and stromal cells. Then, the Ph(+) cells escape to the negative rea regulation induced by cell-cell interaction. Moreover, a primary effect of Bcr-Abl expression is to prolong cell survival by suppression of apoptosis. These models are not sufficient to give a complete explanation of the molecular deregulation mediated by Bcr-Abl. However, they increase our knowledge of the implication of the oncoprotein in the pathogenesis of CML. Further studies will undoubtedly identify new disregulated pathways involved in the transformed phenotype. These progresses ma!: lead to tile development of a suitable therapy.