Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease with distinct biological and clinical features. The biologic basis of the stereotypical progression from chronic phase through accelerated phase to blast crisis is poorly understood. We used DNA microarrays to compare gene expression in 91 cases of CML in chronic (42 cases), accelerated (17 cases), and blast phases (32 cases). Three thousand genes were found to be significantly (P < 10(-10)) associated with phase of disease. A comparison of the gene signatures of chronic, accelerated, and blast phases suggest that the progression of chronic phase CML to advanced phase (accelerated and blast crisis) CML is a two-step rather than a three-step process, with new gene expression changes occurring early in accelerated phase before the accumulation of increased numbers of leukemia blast cells. Especially noteworthy and potentially significant in the progression program were the deregulation of the WNT/beta-catenin pathway, the decreased expression of Jun B and Fos, alternative kinase deregulation, such as Arg (Abl2), and an increased expression of PRAME. Studies of CML patients who relapsed after initially successful treatment with imatinib demonstrated a gene expression pattern closely related to advanced phase disease. These studies point to specific gene pathways that might be exploited for both prognostic indicators as well as new targets for therapy.