Chronic myelogenous leukemia is a fatal disorder that is characterized by a specific genetic anomaly ¿ the Philadelphia chromosome. Imatinib is a new drug that is very effective in CML. However, Imatinib is much less effective in more advanced phases of CML, and even some patients treated early with Imatinib will develop resistance to this drug. The mechanism of resistance to this drug is unknown. Our laboratory studies a process called silencing, whereby a gene can no longer be utilized in a given cell or condition. Silencing is used by cancer cells to turn off some genes, and we propose here that silencing is one of the mechanism of Imatinib resistance in CML. To test this, we will measure DNA methylation ¿ a biochemical mark of silencing ¿ in CML patients treated with Imatinib, and we will correlate methylation with response to the drug. Ultimately, we hope to be able to identify those patients who will not respond to this therapy. There are drugs currently in clinical trials that can reverse methylation and silencing. We also propose here to test the efficacy of one such drug ¿ decitabine, in reversing resistance to Imatinib in CML. In a clinical trial, we will treat patients with known resistance to Imatinib with decitabine followed by Imatinib, and determine the efficacy of this approach. In parallel, we will collect samples from the patients enrolled on the trial, test them to verify that methylation and silencing were reversed, and correlate the extent of these molecular effects with the response to the agents. Ultimately, this work aims at increasing the cure rate for CML by overcoming resistance to Imatinib.