Zhou Qing-Bing, Du Yu, Zhang Shan-Shan, Liu Zheng-Tang, Ma Rou, Xu Yong-Gang
Institute of Geriatric Medicine, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, People's Republic of China.
Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, People's Republic of China.
Cancer Manag Res. 2021 Jan 7;13:55-63. doi: 10.2147/CMAR.S280886. eCollection 2021.
DNA methylation is known to play an important role in myelodysplastic syndrome (MDS). We previously showed that Chinese herbs (CHs) containing realgar (AsS) 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 ( = 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) ( < 0.0001). Two hypermethylated and two hypomethylated genes were selected for validation by pyrosequencing (all < 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.
已知DNA甲基化在骨髓增生异常综合征（MDS）中起重要作用。我们之前表明，含雄黄（AsS）的中药对治疗伴有多系发育异常的MDS（MDS-MLD）有效。我们测试了MDS-MLD患者对中药治疗的反应是否与DNA甲基化变化有关。
首先，使用Illumina甲基化850K芯片检测法评估8例MDS-MLD患者和3名健康供者骨髓细胞的预处理甲基化状态。然后，8例MDS-MLD患者接受中药治疗6个月，治疗后测量砷浓度。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芯片数据。
8例MDS-MLD患者中有5例显示血液学改善（有效治疗组），而3例显示疾病进展（无效治疗组）（阳性反应率：62.5%）。患者体内砷浓度范围为26.60至64.16μg/L（中位数48.4μg/L），两组之间无显著差异（P = 0.27）。与健康对照相比，无效治疗组中有3个基因低甲基化，110个基因高甲基化。然而，在血液学改善组中，有102个基因显著低甲基化，87个基因高甲基化。有效治疗组低甲基化位点的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2个高甲基化基因和2个低甲基化基因通过焦磷酸测序进行验证（均P < 0.05）。
MDS-MLD患者可能呈现不同的DNA甲基化亚型。含雄黄的中药可能对治疗低甲基化亚型的MDS-MLD患者有效。
