Chronic myeloid leukemia (CML) is probably the most extensively studied human malignancy. The discovery of the Philadelphia (Ph) chromosome in 19601 as the first consistent chromosomal abnormality associated with a specific type of leukemia was a breakthrough in cancer biology. It took 13 years before it was appreciated that the Ph chromosome is the result of at (9; 22) reciprocal chromosomal translocation2 and another 10 years before the translocation was shown to involve the ABL proto-oncogene normally on chromosome 93 and a previously unknown gene on chromosome 22, later termed BCR for breakpoint cluster region. 4 The deregulated Abl tyrosine kinase activity was then defined as the pathogenetic principle, 5 and the first animal models were developed. 6 The end of the millennium sees all this knowledge transferred from the bench to the bedside with the arrival of Abl-specific tyrosine kinase inhibitors that selectively inhibit the growth of BCR-ABL–positive cells in vitro7, 8 and in vivo. 9

In this review we will try to summarize what is currently known about the molecular biology of CML. Because several aspects of CML pathogenesis may be attributable to the altered function of the 2 genes involved in the Ph translocation, we will also address the physiological roles of BCR and ABL. We concede that a review of this nature can never be totally comprehensive without losing clarity, and we therefore apologize to any authors whose work we have not cited.