Clinical Response to Traditional Chinese Herbs Containing Realgar (As(2)S(2)) is Related to DNA Methylation Patterns in Bone Marrow DNA from Patients with Myelodysplastic Syndrome with Multilineage Dysplasia.
Clinical Response to Traditional Chinese Herbs Containing Realgar (As(2)S(2)) is Related to DNA Methylation Patterns in Bone Marrow DNA from Patients with Myelodysplastic Syndrome with Multilineage Dysplasia.
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DOI：
10.2147/cmar.s280886
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发表时间：
2021
影响因子：
3.3
通讯作者：
Xu YG
中科院分区：
文献类型：
--
作者：
Zhou QB;Du Y;Zhang SS;Liu ZT;Ma R;Xu YG
DNA甲基化在骨髓增生异常综合征（MDS）中起重要作用。我们以前的研究表明，含雄黄（As 2S 2）的中药（CHs）在治疗MDS伴多系发育不良（MDS-MLD）方面是有效的。我们测试了对CH治疗的反应是否与MDS-MLD中DNA甲基化的变化有关。首先，使用Illumina甲基化850 K阵列BeadChip测定来评估来自8名MDS-MLD患者和3名健康供体的骨髓细胞中的预处理甲基化状态。8例MDS-MLD患者用CHs治疗6个月，治疗后测定砷浓度。随后将患者分为“有效”和“无效”治疗反应组，并比较两组的DNA甲基化模式。最后，通过焦磷酸测序验证BeadChip数据。8例MDS-MLD患者中有5例血液学改善（有效治疗组），3例疾病进展（无效治疗组）（阳性应答率：62.5%）。患者的砷浓度范围为26.60至64.16 μg/L（中位数为48.4 μg/L），两组之间无显著差异（p = 0.27）。与健康对照组相比，无效治疗组有3个基因低甲基化，110个基因高甲基化。然而，在血液学改善的组中，102个基因明显低甲基化，87个基因高甲基化。有效治疗组的低甲基化位点比例高于无效治疗组（分别为53.9%和2.6%;卡方检验）（p < 0.0001）。选择两个高甲基化和两个低甲基化基因用于通过焦磷酸测序进行验证（所有p < 0.05）。MDS-MLD患者可能存在不同的DNA甲基化亚型。含雄黄的中药复方制剂可能对低甲基化型MDS-MLD患者有效。
DNA methylation is known to play an important role in myelodysplastic syndrome (MDS). We previously showed that Chinese herbs (CHs) containing realgar (As2S2) were effective at treating MDS with multilineage dysplasia (MDS–MLD). We tested whether the response to CH treatment was related to changes in DNA methylation in MDS–MLD. First, the Illumina methylation 850K array BeadChip assay was used to assess the pretreatment methylation status in bone marrow cells from eight MDS–MLD patients and 3 healthy donors. The eight MDS–MLD patients were then treated with CHs for six months, the arsenic concentration was measured following treatment. The patients were subsequently divided into “effective” and “ineffective” treatment response groups and the DNA methylation patterns of the two groups were compared. Finally, the BeadChip data were validated by pyrosequencing. Five of the eight MDS–MLD patients showed hematological improvement (effective-treatment group), while three showed disease progression (ineffective-treatment group) (positive response rate: 62.5%). The arsenic concentrations in the patients ranged from 26.60 to 64.16 μg/L (median 48.4 μg/L) and were not significantly different between the two groups (p = 0.27). Compared with the healthy controls, three genes were hypomethylated and 110 were hypermethylated in the ineffective-treatment group. However, in the group showing hematological improvement, 102 genes were markedly hypomethylated and 87 hypermethylated. The effective-treatment group had a higher proportion of hypomethylated sites than the ineffective-treatment group (53.9% vs 2.6%, respectively; chi-square test) (p < 0.0001). Two hypermethylated and two hypomethylated genes were selected for validation by pyrosequencing (all p < 0.05). MDS–MLD patients may present different DNA methylation subtypes. CHs containing realgar may be effective for treating MDS–MLD patients with the hypomethylation subtype.