Gene expression changes associated with progression and response in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a hematopoetic stem cell disease with distinct biological and clinical features. The biological foundation 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 the progression from chronic to blast phase. A comparison of the gene signatures of chronic, accelerated, and blast phases suggest that the progression of chronic phase CML from chronic 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 leukemia blast cells. The genetic signature of advanced phase CML is similar to that of normal CD34+ cells; however, progression also involved novel genes not expressed in normal CD34+ cells. Especially noteworthy is deregulation of the WNT/b-catenin pathway, the decreased expression of both JunB and Fos, and dysregulation of genes under the control of MZF1 and delta EF1 zinc finger transcription factors. Studies of CML patients who relapsed after initially successful treatment with imatinib mesylate demonstrated a gene expression pattern closely related to advanced phase disease. Take together, these data suggest that CML progression begins relative early and before clinical and pathological detection, and features distinct genetic differences compared to normal hematpoetic cells that might provide diagnostic and therapeutic targets. Samples from different phases of CML were hybridized against the pool of chronic phases of samples.