Low level CpG island promoter methylation predicts a poor outcome in adult T-cell acute lymphoblastic leukemia

Abstract : Cancer cells undergo massive alterations in their DNA methylation patterns which result in aberrant gene expression and malignantphe notypes. Abnormal DNA methylation is a prognostic marker in several malignancies, but its potential prognostic signifi cance in adult T-cel lacute lymphoblastic leukemia is poorly defined. Here, we performed methylated DNA immunoprecipitation to obtain a comprehensive genome-wide analysis of promoter methylation in adult T-cell Acute Ly mphoblastic Leukemia (n=24) compared to normal thym i (n=3). We identified a CpG hypermethylator phenotype that distinguishes two T-cell acute lymphoblastic leukemia subgroups and further validate it in an independent series of 17 T-L ymphoblastic Lymphoma. Next, we identified a methylation classifier based on 9 promoters which accurately predict the methylation phenotype. This classifier was applied to an independent series of 168 primary adult T-cell Acute Lymphoblastic Leukemias treated accordingly to the GRAAL L03/05 trial using methyl ation-spec ific multiplex ligation-dependent probe amplification. Importantly hypomethylation correl ated with s pecific oncogenic s ubtypes of T-cell Acute Lymphoblastic Leukemias and identified patients associated with a poor clinical outcome. This methylation -specific multiplex ligation-dependent probe amplification based methylation profiling could be useful for therapeutic stratification of adult T-cell Acute Lymphoblastic Leukemias in routine practice.