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 bcr abl chimeric fusion gene generated by the Philadelphia chromosome tran slocation in chronic myelogenous leukemia (CML), structure function st udies quickly identified which parts of this molecule were playing a r ole in the generation of the phenotypes of growth factor independent g rowth, anchorage independent growth, and genetic instability which are associated with this disease. These latter changes result in abnormal ly high levels of mature myeloid elements circulating in the systemic circulation of CML patients. In addition, the genetic instability whic h is associated with the presence of the Philadelphia chromosome drive s the evolution of the disease from an indolent chronic non life-threa tening leukemia, to a fulminant acute leukemic syndrome which results in the death of patients from bleeding and infection. Multiple sites o f contact between the p210(bcrabl) and its substrates have already bee n identified which are relevant to the phenotypic changes characterist ic of CML cells and define their response to therapy. In this review, we will discuss what is known about the relationships between the stru ctural domains of the p210(bcrabl) protein and the characteristics of the disease process which it causes. We will also discuss how this inf ormation may be applied to the establishment of new directions in ther apy.