  Chronic Myeloid Leukemia (CML) is a biphasic malignant clonal disorder that
progresses, first with a chronic phase, where the cells have enhanced
proliferation only, and then to a blast phase, where the cells have the ability
of self-renewal. It is well-recognized that the Philadelphia chromosome (which
contains the BCR-ABL fusion gene) is the "hallmark of CML". However, empirical
studies have shown that the mere presence of BCR-ABL may not be a sufficient
condition for the development of CML, and further modifications related to
tumor suppressors may be necessary. Accordingly, we develop a three-mutation
stochastic model of CML progression, with the three stages corresponding to the
non-malignant cells with BCR-ABL presence, the malignant cells in the chronic
phase and the malignant cells in the blast phase. We demonstrate that the model
predictions agree with age incidence data from the United States. Finally, we
develop a framework for the retrospective estimation of the time of onset of
malignancy, from the time of detection of the cancer.
