A Pilot Study of Aberrant CpG Island Hypermethylation of SPRED1 in Acute Myeloloid Leukemia
A Pilot Study of Aberrant CpG Island Hypermethylation of SPRED1 in Acute Myeloloid Leukemia
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急性髓系白血病 SPRED1 异常 CpG 岛高甲基化的初步研究
DOI：
10.7150/ijms.27757
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发表时间：
2019-01-01
影响因子：
3.6
通讯作者：
Zhang, Rui
中科院分区：
文献类型：
--
作者：
Sun, Jingwen;Zhang, Jinjing;Zhang, Rui
背景：肿瘤抑制基因的表观遗传沉默在急性髓性白血病（AML）中起重要作用。最近，SPRED1， RAS MAPK通路的负调节因子，被确定为AML中下调的肿瘤抑制因子。然而，对于其在AML中的潜在失调知之甚少。在这项研究中，我们研究了AML中SPRED1启动子的甲基化状态及其与mRNA水平的关系。方法：在16例非急性早发性粒细胞白血病（non-APL）患者和3例使用Sequenom MassARRAY平台诱导治疗后获得完全缓解的患者中，测量SPRED1四个区域（#1:310 bp类似于723 bp， #2: 810 bp类似于1299 bp， #3: 1280 bp类似于1742 bp和#4:1715 bp类似于2059 bp）的甲基化水平。采用实时定量聚合酶链反应（q-RT PCR）分析SPRED1 mRNA水平。结果：AML患者在#1_CpG_1区（p = 0.04）和#1_CpG_11区（p = 0.002）的平均甲基化水平显著高于对照组。AML患者#1_CpG_11甲基化值与mRNA水平呈负相关（r = -0.558, p = 0.013），但#1_CpG_1甲基化状态与mRNA水平无显著相关性（r = -0.103, p = 0.675）。两组患者的甲基化水平与临床生化指标及治疗效果比较差异无统计学意义（p < 0.05）。表观遗传调控基因如DNMT3A、TET2和IDH1/2的突变在甲基化水平较高的患者中最常见。三名完全缓解的患者甲基化水平下降。结论：SPRED1启动子区域的异常甲基化状态与AML中基因转录的下调有关。甲基化水平可能与AML的治疗反应有关。SPRED1的表观遗传畸变可能与表观遗传调控基因的突变有关。
Background: Epigenetic silencing of tumor suppressor genes plays important role in acute myeloid leukemia (AML). Recently, SPRED1, a negative regulator of the RAS MAPK pathway, is identified as a tumour suppressor downregulated in AML. However, little is known regarding its underlying dysregulation in AML. In this study, we investigated methylation status of SPRED1 promoters and their association with mRNA levels in AML.Methods: Methylation level were measured in four regions of SPRED1 (#1: 310 bp similar to 723 bp, #2: 810 bp similar to 1299 bp, #3: 1280 bp similar to 1742 bp and #4: 1715 bp similar to 2059 bp) in a total of 16 patients with de novonon-acute promyelocytic leukemia (non-APL) and three patients who got complete remission after induction treatment using the Sequenom MassARRAY platform. Quantitative real-time polymerase chain reaction (q-RT PCR) was used to analyze SPRED1 mRNA levels.Results: AML patients had a significantly higher average methylation level than controls at regions of #1_CpG_1 (p = 0.04) and #1_CpG_11 (p = 0.002). The methylation values for #1_CpG_11 were negatively correlated with mRNA levels (r = -0.558, p = 0.013) but there was no significant association between #1_CpG_1 methylation status and mRNA levels ( r = -0.103, p = 0.675) in AML patients. There was no significant difference in the methylation level when comparing with clinical biochemical parameters and treatment response (p > 0.05). Mutations of epigenetic regulation genes such as DNMT3A, TET2 and IDH1/2 were most frequently observed in patients with higher methylation levels. Decreased methylation levels were revealed in three patients who got complete remission.Conclusions: Aberrant methylation statuses of the SPRED1 promoter regions are associated with the downregulation of gene transcription in AML. The methylation level is probably associated with the treatment response of AML. Mutations of epigenetic regulation genes might be involved in the epigenetic aberration of SPRED1.