Resistance to Imatinib mesylate is emerging as a real clinical problem in the management of chronic myelogenous leukemia (CML). In this project, we are exploring the hypothesis that epigenetic silencing associated with promoter DNA methylation mediates resistance in selected cases, and that reversal of silencing by decitabine-induced hypomethylation can be of therapeutic benefit in CML. In progress to date, we have identified samples from patients with CML prior to Imatinib therapy, as well as from patients with established resistance to Imatinib. Bisulfite based analysis identified methylation of p15 and CDH13 in subsets of patients but ruled these genes out as major causes of resistance. In parallel, clinical trials of decitabine have shown activity as single agent and when combined with Imatinib in CML resistant to Imatinib. Analysis of samples from patients on trial showed hypomethylation after therapy. Flypomethylation dynamics suggest that decitabine leads to CML cell death 5-10 days after treatment and suggest that resistance to decitabine is not pharmacologic. These studies are ongoing to clarify the role of methylation in the pathogenesis and therapy of Imatinib resistant CML.
