Chaber Radosław, Gurgul Artur, Wróbel Grażyna, Haus Olga, Tomoń Anna, Kowalczyk Jerzy, Szmatoła Tomasz, Jasielczuk Igor, Rybka Blanka, Ryczan-Krawczyk Renata, Duszeńko Ewa, Stąpor Sylwia, Ciebiera Krzysztof, Paszek Sylwia, Potocka Natalia, Arthur Christopher J, Zawlik Izabela
Institute of Nursing and Health Sciences, Faculty of Medicine, University of Rzeszow, Rzeszow, Poland.
National Research Institute of Animal Production, Laboratory of Genomics, Balice, Poland.
PLoS One. 2017 Nov 10;12(11):e0187422. doi: 10.1371/journal.pone.0187422. eCollection 2017.
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.
除了基因改变外，表观遗传异常已被证明是急性淋巴细胞白血病（ALL，最常见的儿童癌症）发病机制的基础。本研究的目的是描绘前体B细胞ALL（BCP ALL）患儿的全基因组DNA甲基化图谱，并将该图谱与正常骨髓样本中观察到的甲基化情况进行比较。我们还进一步努力将观察到的甲基化模式与选定的临床特征相关联。我们使用Infinium MethylationEPIC BeadChip Array评估了38例BCP ALL患儿诊断时骨髓样本的DNA甲基化情况，并以4份正常骨髓细胞样本作为对照。患者根据BFM ALL IC 2009方案进行诊断并分层为预后组。对全基因组差异甲基化位点以及启动子甲基化图谱的分析使得白血病样本和对照样本能够清晰地分为两个簇。86.6%的启动子相关差异甲基化位点在BCP ALL中发生高甲基化。发现7个位点与BFM ALL IC 2009高危组相关。其中，一个位于MBP基因的基因体内，另一个位于PSMF1基因的启动子区域内。差异甲基化位点与ETV6-RUNX1融合和超二倍体患者亚组显著相关。分析的易位和基因序列背景的变化不影响甲基化，甲基化似乎不是调节所得融合基因表达的机制。
