The study of oncogene activation in naturally occurring human leukemias provides a useful approach to define the range of growth regulatory mechanisms used by hematopoietic stem cells. Recent analysis of the structural changes created by the Philadelphia chromosome translocation [t(9;22) — (q34;q11)] shows that two alternative regions of the BCR gene on chromosome 22 can be used as the breakpoint site. This results in two alternative subsets of exons of the BCR gene remaining on the Philadelphia chromosome, which can be joined by RNA splicing to a common set of exons of the ABL oncogene derived from chromosome 9 sequences. The resulting chimeric mRNAs encode a 210,000 MW protein in CML (P210BCR/ABL) and a 185,000 MW protein in ALL (P185BCR/ABL). Both proteins retain an active tyrosine kinase activity derived from the ABL portion.