Cml Biology for the Clinician

represents the most important advance in clinical oncology in the last decade—not only because of the magnitude of the difference (a more than 40% increase in 5-year survival over that with previously available therapies) 1, but also because of the means by which that increase occurred. In this sense, cml represents a model disease for oncology, with the Philadelphia chromosome being the first chromosomal translocation (and therefore genetic defect) identifiable in any human cancer 2; the first human fusion-activated oncogene, by identification of Bcr-Abl as the translocation product 3; the first cancer treated with targeted small-molecule therapy (imatinib, beginning in 1999); and the first disease in which a gene-based test to monitor disease bulk became a standard of clinical practice 1. Other tyrosine kinase inhibitors (tkis) that are more potent against Bcr-Abl are now available or in development. Furthermore, the apparent long-term persistence of disease for many years despite excellent control represents the most obvious clinical correlate of the currently dominant, but still controversial, model of cancer stem cell biology, whose explanation for that persistence is the fact that the targeted therapy hits the differentiated progeny of the cml stem cell, which itself is immune to that therapy. Despite the many hidden biological and biochemical cellular complexities, the conceptual simplicity of that model is pedagogically pleasing and can easily be presented to non-oncology colleagues, medical students, patients and their families, and the mass media. However, as the English economist John Maynard Keynes noted, we are all prisoners of our implicit metaphysics, and clinicians are prisoners of the models they carry in their heads of the diseases that they treat. The present article therefore examines several features of that model and points out where the current understanding of the cell biology and biochemistry of cml and Bcr-Abl indicate that parts of the model may be oversimplified or even wrong. Each of the new insights has implications for the prognosis and therapy of cml (and, by extension, other malignancies). ABSTRACT