DNA-methylation-based characterization of T-cell acute lymphoblastic leukemia correlated well with genetic features, differentiation stages, and prognosis

Abstract

The development of next-generation sequencing technologies has enabled the genome-wide analysis of pediatric T-cell acute lymphoblastic leukemia (T-ALL) and unveiled its clinicopathological features. In recent years, epigenetic profiles of T-ALL such as DNA methylation status have been widely investigated. In this study, we performed methylation array analysis in 79 pediatric T-ALL patients using EPIC methylation arrays. On the basis of DNA methylation profiles, pediatric T-ALL was classified into 4 clusters (Clusters 1–4). Cluster 1 was related to TAL1. Patients in this cluster showed high expression levels of ALDH1A2, a TAL1 downstream gene, and exhibited a late cortical thymocyte profile. Cluster 2 represented the earliest stage of T-cell development (CD4/8 double negative) and was characterized by high DEPTOR expression levels leading to PI3K-AKT activation. Interestingly, DNA methylation profiles were completely opposite between Clusters 1 and 2. In the hypermethylated Cluster 3, mutations of epigenetic regulators and JAK-STAT-related genes were frequently detected. All Cluster 3 patients were alive, but the significance of this finding should be interpreted carefully because of the small sample size (n=11). Cluster 4 was associated with SPI1 and showed the hypomethylated status. In addition to SPI1-related genes, high expression levels of cell-proliferation- and RAS/MAPK-related genes were the characteristic findings. All patients with SPI1 fusion, which we reported to have an extremely dismal prognosis, were classified into Cluster 4 with two dead patients without SPI1 fusions. Thus, Cluster 4 patients represented fatal outcomes regardless of SPI1 fusion. In the future, the elucidation of these genetic and epigenetic profiles might be helpful for a more adequate risk stratification and a new therapeutic strategy for T-ALL.