By comparison with some common malignancies, CML is rare and thus hardly a major general health problem. Nonetheless, the disease has served as a pacemaker in many aspects of cancer biology and therapy. CML was the first malignant disorder in which a consistent association with a chromosomal abnormality was demonstrated. Ph, described by Nowell and Hungerford in 1960 (4), was originally thought to represent a shortened chromosome 22 (22q-). Subsequent studies revealed, however, that Ph is the result of a reciprocal translocation between chromosomes 9 and 22 (5). This translocation was shown to fuse sequences of the ABL gene from chromosome 9q34 downstream of BCR on chromosome 22q11, generating a chimeric BCR-ABL gene, which represented the first demonstration of an oncogenic fusion gene (6,7). Shortly thereafter, the Bcr-Abl protein was shown to exhibit constitutive tyrosine kinase activity that was correlated with cellular transformation, and provided the rationale for the development of specific kinase inhibitors for therapeutic use (8). These efforts eventually led to the discovery of imatinib, the success of which has fundamentally changed the management of CML, while at the same time establishing molecularly targeted therapy as a new paradigm in oncology, with implications much beyond the realm of CML. The direct line, from the presence of a specific causal genetic abnormality BCR-ABL to its specific targeted therapy, has led the World Health Organization to define CML as a myeloproliferative disorder with a BCR-ABL fusion gene (9), and to refer to the BCR-ABL-negative disease as atypical CML (aCML), even in cases that are morphologically indistinguishable. It is likely that this sets off another paradigm, in the sense that the molecular rather than the morphologic or the organ-of-origin based criteria will form the basis of oncological disease classification in the future.
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