Abstract

BackgroundAlthough aberrant DNA methylation has been observed previously in acute lymphoblastic leukemia (ALL), the patterns of differential methylation have not been comprehensively determined in all subtypes of ALL on a genome-wide scale. The relationship between DNA methylation, cytogenetic background, drug resistance and relapse in ALL is poorly understood.ResultsWe surveyed the DNA methylation levels of 435,941 CpG sites in samples from 764 children at diagnosis of ALL and from 27 children at relapse. This survey uncovered four characteristic methylation signatures. First, compared with control blood cells, the methylomes of ALL cells shared 9,406 predominantly hypermethylated CpG sites, independent of cytogenetic background. Second, each cytogenetic subtype of ALL displayed a unique set of hyper- and hypomethylated CpG sites. The CpG sites that constituted these two signatures differed in their functional genomic enrichment to regions with marks of active or repressed chromatin. Third, we identified subtype-specific differential methylation in promoter and enhancer regions that were strongly correlated with gene expression. Fourth, a set of 6,612 CpG sites was predominantly hypermethylated in ALL cells at relapse, compared with matched samples at diagnosis. Analysis of relapse-free survival identified CpG sites with subtype-specific differential methylation that divided the patients into different risk groups, depending on their methylation status.ConclusionsOur results suggest an important biological role for DNA methylation in the differences between ALL subtypes and in their clinical outcome after treatment.

Highlights

  • Aberrant DNA methylation has been observed previously in acute lymphoblastic leukemia (ALL), the patterns of differential methylation have not been comprehensively determined in all subtypes of ALL on a genome-wide scale

  • The DNA methylation landscape in ALL HumanMethylation 450k BeadChips were used for quantitative DNA methylation analysis of leukemic blasts from pediatric ALL patients in the Nordic countries

  • We included age-matched bone marrow (BM) samples collected at remission from 86 of the ALL patients as control samples

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Summary

Introduction

Aberrant DNA methylation has been observed previously in acute lymphoblastic leukemia (ALL), the patterns of differential methylation have not been comprehensively determined in all subtypes of ALL on a genome-wide scale. The majority of CpG sites are methylated. Pediatric acute lymphoblastic leukemia (ALL) originates from the malignant transformation of lymphocyte progenitor cells into leukemic cells in the B-cell and T-cell lineages. ALL is a heterogeneous disease, in which patients are stratified into subtype groups based on their cellular immunophenotype and recurrent cytogenetic aberrations, such as aneuploidies and translocations, acquired by the leukemic cells [5,6]. In the Nordic countries, the five-year survival rate for pediatric ALL patients exceeds 80%, but one-fifth of the patients relapse despite continued chemotherapy [5]. The cytogenetic aberrations are indicative of better or poorer relapse-free survival rates, relapses occur in all cytogenetic subtypes [6]

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