[Philadelphia translocation and the human c-abl oncogene--relations in the light of molecular genetics]

Application of recombinant DNA techniques led to the characterization of a heterogenous group of evolutionary conserved genes with potential transforming activity, called oncogenes. Regularly they seem to be involved in normal cell proliferation and differentiation. Various mechanisms including an increased dosage of gene product as well as subtile point mutations activate these sequences to oncogenes sensu strictu. Molecular analysis of the Philadelphia translocation in leukemic cells of CML-patients revealed a consistent translocation of the human c-abl-oncogene from chromosome 9 to the Ph1-chromosome, regardless of the cytogenetic subtype. Moreover we could demonstrate individual breakpoints for every patient investigated so far. However, these breakpoints are clustered on chromosome 22 within sequences of the bcr-gene. In leukemic cells containing the rearranged-c-abl/bcr sequences a new transcript is detected which is possibly the mRNA for an altered c-abl-protein that unmasks associated tyrosine specific kinase activity. These gene rearrangements were not detected in Ph1-negative CML-patients. Another human oncogene, c-sis, is located on chromosome 22, but seems not to play a crucial role in the generation of CML. These results are discussed in the context of recent advances in oncogene-research.