The presence of a BCR-ABL1 fusion, usually in conjunction with a raised leukocyte count and other less specific clinical and hematological features, defines chronic myeloid leukemia (CML). Because the BCR-ABL1 gene is a very consistent finding, one might have expected the leukemia to run a very similar course in different patients, but this is conspicuously not the case. This conclusion is based both on clinical observations and the results of laboratory studies, which are explained further in the paper. If the notion of intrinsic heterogeneity is accepted, there are a number of possible causes that may act independently or in various combinations (Table 1). Perhaps the most obvious, which will not be considered further in this paper, is the possibility that there exists a molecular event that precedes and predisposes to the acquisition of the BCR-ABL fusion gene; one would also have to postulate that this preceding lesion, for which there is only circumstantial evidence available from a study of a limited number of patients,1'2 also influences the clinical expression of the leukemia. Another possibility, which will also not be considered here, is that the BCR-ABL1-positive clone has the propensity to acquire new genetic events, presumably as a result of 'genetic instability', and that the degree of this genetic instability varies from patient to patient. The notion that the BCR-ABL1-positive clone is in fact predisposed to further genetic change is indeed widely accepted, although there is no evidence for any differing degrees of genetic instability in different patients.
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