Antagonistic effects of ABL and BCRABL proteins on proliferation and the response to genotoxic stress in normal and leukemic myeloid cells

Following the discovery of the p210(bcrabl) protein product of the bcrabl chimeric fusion gene generated by the Philadelphia chromosome translocation in chronic myelogenous leukemia (CML), structure function studies quickly identified which parts of this molecule were playing a role in the generation of the phenotypes of growth factor independent growth, anchorage independent growth, and genetic instability which are associated with this disease. These latter changes result in abnormally high levels of mature myeloid elements circulating in the systemic circulation of CML patients. In addition, the genetic instability which is associated with the presence of the Philadelphia chromosome drives the evolution of the disease from an indolent chronic non life-threatening leukemia, to a fulminant acute leukemic syndrome which results in the death of patients from bleeding and infection. Multiple sites of contact between the p210(bcrabl) and its substrates have already been identified which are relevant to the phenotypic changes characteristic of CML cells and define their response to therapy. In this review, we will discuss what is known about the relationships between the structural domains of the p210(bcrabl) protein and the characteristics of the disease process which it causes. We will also discuss how this information may be applied to the establishment of new directions in therapy.