Whole-genome DNA methylation characteristics in pediatric precursor B cell acute lymphoblastic leukemia (BCP ALL).

Radosław Chaber,Christopher J Arthur,Natalia Potocka,Igor Jasielczuk,Ewa Duszeńko,Renata Ryczan-Krawczyk,Jerzy Kowalczyk,Izabela Zawlik,Grażyna Wróbel,Anna Tomoń,Krzysztof Ciebiera,Sylwia Stąpor,Sylwia Paszek,Tomasz Szmatoła,Blanka Rybka,Olga Haus,Artur Gurgul,Obul Reddy Bandapalli

doi:10.1371/journal.pone.0187422

Abstract

In addition to genetic alterations, epigenetic abnormalities have been shown to underlie the pathogenesis of acute lymphoblastic leukemia (ALL)—the most common pediatric cancer. The purpose of this study was to characterize the whole genome DNA methylation profile in children with precursor B-cell ALL (BCP ALL) and to compare this profile with methylation observed in normal bone marrow samples. Additional efforts were made to correlate the observed methylation patterns with selected clinical features. We assessed DNA methylation from bone marrow samples obtained from 38 children with BCP ALL at the time of diagnosis along with 4 samples of normal bone marrow cells as controls using Infinium MethylationEPIC BeadChip Array. Patients were diagnosed and stratified into prognosis groups according to the BFM ALL IC 2009 protocol. The analysis of differentially methylated sites across the genome as well as promoter methylation profiles allowed clear separation of the leukemic and control samples into two clusters. 86.6% of the promoter-associated differentially methylated sites were hypermethylated in BCP ALL. Seven sites were found to correlate with the BFM ALL IC 2009 high risk group. Amongst these, one was located within the gene body of the MBP gene and another was within the promoter region- PSMF1 gene. Differentially methylated sites that were significantly related with subsets of patients with ETV6-RUNX1 fusion and hyperdiploidy. The analyzed translocations and change of genes’ sequence context does not affect methylation and methylation seems not to be a mechanism for the regulation of expression of the resulting fusion genes.

Highlights

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer with 3–5 cases per 100,000 with a peak of incidence 2–5 years [1]
Genetic changes with good prognosis include hyperdiploidy with greater than 50 chromosomes or translocation t(12;21) ETV6-RUNX1 (TEL-AML1) which are detected in about a quarter of cases of childhood B-cell ALL (BCP ALL) [4]
After normalization for technical variation, singular value decomposition method (SVD) indicated that the only source of variation amongst the sample groups was inter-group differentiation

Summary

Introduction

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer with 3–5 cases per 100,000 with a peak of incidence 2–5 years [1]. Most of these cases (80–85%) originate from precursor B cells, BCP ALL [2]. The initiation of BCP ALL (as with other ALL’s) is driven by genetic alterations including point mutations, chromosome amplifications or translocations which lead to abnormal expression of key genes responsible for cell proliferation and differentiation [3]. Leukemic cells in ~75% of patients contain some chromosome abnormalities. Some of these abnormalities have prognostic significance. There are chromosomal abnormalities as t(1;19)(q23;p13) or TCF3-PBX1 (formerly known as E2A-PBX1) (4% cases) with uncertain prognostic significance [4,5]

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