CML is defined by the presence of a BCR-ABL fusion gene that gives rise to a cognate chimerical protein with constitutive tyrosine kinase activity. Cytogenetically, the BCR-ABL translocation is evident as a Ph chromosome, but some 5% of patients have a cryptic translocation that is detectable only by FISH or RT-PCR. It is thought that the BCR-ABL translocation occurs in a pluripotent hematopoietic stem cell and is the only event required for the induction of chronic phase CML, although this has been questioned. Bcr-Abl tyrosine kinase activity maintains a complicated and redundant network of signaling pathways, individual components of which are frequently dispensable for malignant transformation. The biological hallmarks of CML cells, increased proliferation, reduced apopto-sis, and perturbed adhesion to extracellular matrix, are almost exclusively dependent on Bcr-Abl's tyro-sine kinase activity, indicating that the latter is an ideal therapeutic target. The mechanisms underlying disease progression are not well understood. Analogy to AML suggests that the function of a transcription factor may be disrupted that is essential for coordinated myeloid cell differentiation.

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