The activation of the cellular oncogene c-abl in chronic myelogenous and acute lymphoblastic leukemias

Chronic myelogenous (CML) and acute lymphoblastic (ALL) leukemias are human malignancies associated with the presence of a chromosomal abnormality involving the activation of a cellular oncogene. The Philadelphia chromosome (Ph'), present in the leukemic cells of over 95% of CML and 25% of ALL cases, results from the fusion of the 5'-truncated oncogene c-abl (normally located on chromosome 9) to a transcriptionally active gene on chromosome 22. The scission on chromosome 22 involves two possible sites of breakpoint clustering: the so-called bcr region for CML and a more 5' DNA segment for ALL. Two distinct chimeric abl proteins, P210 in CML and P190 in ALL, originate from the two resulting hybrid loci. Both proteins are endowed with constitutively high tyrosine kinase activity. Since tyrosine phosphorylation has been implicated in the control of cell growth, it is proposed that the two c-abl variants are causally involved in the development of the two clinically distinct but related diseases.