Hematology Laboratory Service, ICO Badalona-Hospital Germans Trias I Pujol, Myeloid Neoplasms Group, Josep Carreras Leukemia Research Institute (IJC), Badalona, Spain.
Departament de Medicina, Universitat Autònoma de Barcelona, Badalona, Spain.
Clin Epigenetics. 2021 Jan 14;13(1):9. doi: 10.1186/s13148-021-01002-y.
Epigenetic therapy, using hypomethylating agents (HMA), is known to be effective in the treatment of high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients who are not suitable for intensive chemotherapy and/or allogeneic stem cell transplantation. However, response rates to HMA are low and there is an unmet need in finding prognostic and predictive biomarkers of treatment response and overall survival. We performed global methylation analysis of 75 patients with high-risk MDS and secondary AML who were included in CETLAM SMD-09 protocol, in which patients received HMA or intensive treatment according to age, comorbidities and cytogenetic.
Unsupervised analysis of global methylation pattern at diagnosis did not allow patients to be differentiated according to the cytological subtype, cytogenetic groups, treatment response or patient outcome. However, after a supervised analysis we found a methylation signature defined by 200 probes, which allowed differentiating between patients responding and non-responding to azacitidine (AZA) treatment and a different methylation pattern also defined by 200 probes that allowed to differentiate patients according to their survival. On studying follow-up samples, we confirmed that AZA decreases global DNA methylation, but in our cohort the degree of methylation decrease did not correlate with the type of response. The methylation signature detected at diagnosis was not useful in treated samples to distinguish patients who were going to relapse or progress.
Our findings suggest that in a subset of specific CpGs, altered DNA methylation patterns at diagnosis may be useful as a biomarker for predicting AZA response and survival.
表观遗传学治疗，使用低甲基化剂（HMA），已知在治疗不适合强化化疗和/或异基因干细胞移植的高危骨髓增生异常综合征（MDS）和急性髓系白血病（AML）患者中是有效的。然而，HMA 的反应率较低，并且需要寻找治疗反应和总生存的预后和预测生物标志物。我们对 75 例高危 MDS 和继发性 AML 患者进行了全球甲基化分析，这些患者被纳入 CETLAM SMD-09 方案，其中患者根据年龄、合并症和细胞遗传学接受 HMA 或强化治疗。
在诊断时进行的全球甲基化模式的无监督分析不能根据细胞类型、细胞遗传学组、治疗反应或患者预后来区分患者。然而，经过监督分析，我们发现了一个由 200 个探针定义的甲基化特征，该特征可以区分对阿扎胞苷（AZA）治疗有反应和无反应的患者，并且还定义了一个由 200 个探针定义的不同甲基化模式，可以根据患者的生存情况来区分患者。在研究随访样本时，我们证实 AZA 降低了全基因组 DNA 甲基化，但在我们的队列中，甲基化程度的降低与反应类型无关。在诊断时检测到的甲基化特征在治疗样本中不能用于区分将要复发或进展的患者。
我们的研究结果表明，在一组特定的 CpG 中，诊断时改变的 DNA 甲基化模式可能作为预测 AZA 反应和生存的生物标志物有用。
