Implicating the bcr/abl Gene in the Pathogenesis of Philadelphia Chromosome-Positive Human Leukemia

Abstract

The hypothesis that the Philadelphia chromosome might have a causative role in human chronic myelogenous leukemia (CML) was validated by the discovery that the human homologue of the v-abl oncogene of Abelson murine leukemia virus (A-MuLV) mapped to chromosome 9q34, precisely the locus disrupted in the formation of the Philadelphia chromosome. The result immediately suggested an etiologic mechanism: the breakpoint of the Philadelphia chromosome might activate the human c-abl homologue to behave as a transforming gene similar to v-abl. The human homologue of a murine leukemia virus oncogene could be activated to play a direct role in the pathogenesis of human leukemia. Deciphering the molecular consequences of the Philadelphia chromosome, translocation has provided substantial evidence to implicate an activated c-abl gene in the etiology of Ph1-positive human leukemia. The presence of a Philadelphia chromosome characterizes the leukemic tissue in over 90% of the patients with chronic myelogenous leukemia. Virtually all of these patients will harbor the molecular hallmark of CML, a detectable rearrangement of the bcr gene in chromosome 22. The c-abl gene can be activated to leukemogenicity by a variety of mechanisms, including fusion with gag sequences, internal deletions, and point mutations.