Adult acute lymphocytic leukemia (ALL) consists of a heterogeneous group of lymphoid malignancies. Treatment is stratified based on the presence of the Philadelphia chromosome (Ph), t(9;22) that occurs in 15% to 25% of patients. The rest of patients (Ph negative ALL) are routinely treated with intensive chemotherapy programs that do not discriminate against specific molecular characteristics. Although initial complete remission rates are in excess of 70%, long-term survival may vary from less than 5% for Ph positive to 35% for Ph negative patients. It is therefore of great importance to develop molecular tools to identify patients at high risk for relapse that may benefit from specific therapeutic interventions. Aberrant DNA methylation of promoter associated CpG islands is frequently observed in ALL. Genes involved directly or indirectly in cell cycle control appear to be particularly targeted in this disease, with methylation of p73, p15 or p57KIP2 occurring in 11% to 34% of patients. Preliminary data suggests that methylation of these genes identifies an ALL group at high risk for relapse that cannot otherwise be identified. Here, we propose the hypothesis that methylation of 2 or 3 genes of a pathway including p73, p15 and p57KIP2 identifies a subgroup of patients with ALL with poor prognosis. To test this hypothesis, we propose the following specific aim: to evaluate the methylation status of p73, p15 and p57KIP2 in a cohort of 300 patients with ALL homogeneously treated at our institution, and correlate this with survival. The sample size will provide enough power to allow for multivariate analysis. Analysis of DNA methylation will be performed using bisulfite PCR methods, and will be confirmed using bisulfite sequencing in selected cases. The implications of this project include the identification of a subgroup of patients with poor prognosis that may benefit from targeted therapies using hypomethylating agents and/or early allogeneic bone marrow transplantation in first complete remission.
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