Genome-wide DNA methylation analysis in pediatric acute myeloid leukemia.
Genome-wide DNA methylation analysis in pediatric acute myeloid leukemia.
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小儿急性髓性白血病的全基因组 DNA 甲基化分析。
DOI：
10.1182/bloodadvances.2021005381
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发表时间：
2022-06-14
期刊：
影响因子：
7.5
通讯作者：
Hayashi, Yasuhide
中科院分区：
文献类型：
--
作者：
Yamato, Genki;Kawai, Tomoko;Shiba, Norio;Ikeda, Junji;Hara, Yusuke;Ohki, Kentaro;Tsujimoto, Shin-Ichi;Kaburagi, Taeko;Yoshida, Kenichi;Shiraishi, Yuichi;Miyano, Satoru;Kiyokawa, Nobutaka;Tomizawa, Daisuke;Shimada, Akira;Sotomatsu, Manabu;Arakawa, Hirokazu;Adachi, Souichi;Taga, Takashi;Horibe, Keizo;Ogawa, Seishi;Hata, Kenichiro;Hayashi, Yasuhide
FLT 3-ITD和PRDM 16高表达诱导儿童AML中STAT 5和AP-1结合位点的甲基化变化。PRDM 16-高表达AML中的低甲基化区域与多个基因组区域的染色质增加相关。我们研究了64例急性髓性白血病（AML）患儿的全基因组DNA甲基化模式。基于与567个最甲基化的胞嘧啶鸟嘌呤二核苷酸（CpG）位点的无监督聚类，将患者分类为与遗传改变相关的4个聚类。聚类1和聚类3的特征在于存在已知的有利预后因素，例如分别具有低MECOM表达的RUNX 1-RUNX 1 T1融合和KMT 2A重排以及双等位基因CEBPA突变（所有8名患者）。聚类2和4包括表现出与不良结果相关的分子特征的患者，即FLT 3的内部串联重复（FLT 3-ITD）、KMT 2A的部分串联重复和PRDM 16高表达。根据FLT 3-ITD+和FLT 3-ITD− AML之间存在显著差异的1243个CpG位点的甲基化值，将患者分为3个聚类：A、B和C。STAT 5结合基序最常见于1243个CpG位点附近。簇A中的所有8名FLT 3-ITD患者均具有高PRDM 16表达并发生不良事件，而其他簇中的7名FLT 3-ITD患者中仅1名发生不良事件。PRDM 16表达水平也与DNA甲基化模式相关，其在PRDM 16/ABL 1 = 0.10的截止值处急剧变化。AML的转座酶可及染色质测序试验支持基因组区域（如HOXB簇基因、SCHIP 1和PRDM 16）周围染色质可及性增强，这与FLT 3-ITD和PRDM 16高表达AML中的DNA甲基化变化相关。我们的研究结果表明，在特定的CpG位点的DNA甲基化水平是有用的，以支持儿童AML患者的遗传改变和基因表达模式。
FLT3-ITD and high PRDM16 expression induced methylation changes at STAT5 and AP-1 binding sites in pediatric AML. Hypomethylated regions in PRDM16-highly expressed AMLs were correlated with enhanced chromatin accessibilities at multiple genomic regions. We investigated genome-wide DNA methylation patterns in 64 pediatric patients with acute myeloid leukemia (AML). Based on unsupervised clustering with the 567 most variably methylated cytosine guanine dinucleotide (CpG) sites, patients were categorized into 4 clusters associated with genetic alterations. Clusters 1 and 3 were characterized by the presence of known favorable prognostic factors, such as RUNX1-RUNX1T1 fusion and KMT2A rearrangement with low MECOM expression, and biallelic CEBPA mutations (all 8 patients), respectively. Clusters 2 and 4 comprised patients exhibiting molecular features associated with adverse outcomes, namely internal tandem duplication of FLT3 (FLT3-ITD), partial tandem duplication of KMT2A, and high PRDM16 expression. Depending on the methylation values of the 1243 CpG sites that were significantly different between FLT3-ITD+ and FLT3-ITD− AML, patients were categorized into 3 clusters: A, B, and C. The STAT5-binding motif was most frequently found close to the 1243 CpG sites. All 8 patients with FLT3-ITD in cluster A harbored high PRDM16 expression and experienced adverse events, whereas only 1 of 7 patients with FLT3-ITD in the other clusters experienced adverse events. PRDM16 expression levels were also related to DNA methylation patterns, which were drastically changed at the cutoff value of PRDM16/ABL1 = 0.10. The assay for transposase-accessible chromatin sequencing of AMLs supported enhanced chromatin accessibility around genomic regions, such as HOXB cluster genes, SCHIP1, and PRDM16, which were associated with DNA methylation changes in AMLs with FLT3-ITD and high PRDM16 expression. Our results suggest that DNA methylation levels at specific CpG sites are useful to support genetic alterations and gene expression patterns of patients with pediatric AML.
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