School of Health Sciences, Faculty of Medicine, Hematology Division, University of Patras, Patras, Greece.
Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
Clin Epigenetics. 2024 Jun 15;16(1):79. doi: 10.1186/s13148-024-01687-x.
As new treatment options for patients with higher-risk myelodysplastic syndromes are emerging, identification of prognostic markers for hypomethylating agent (HMA) treatment and understanding mechanisms of their delayed and short-term responses are essential. Early fetal hemoglobin (HbF) induction has been suggested as a prognostic indicator for decitabine-treated patients. Although epigenetic mechanisms are assumed, responding patients' epigenomes have not been thoroughly examined. We aimed to clarify HbF kinetics and prognostic value for azacytidine treated patients, as well as the epigenetic landscape that might influence HbF re-expression and its clinical relevance.
Serial HbF measurements by high-performance liquid chromatography (n = 20) showed induction of HbF only among responders (p = 0.030). Moreover, HbF increase immediately after the first azacytidine cycle demonstrated prognostic value for progression-free survival (PFS) (p = 0.032, HR = 0.19, CI 0.24-1.63). Changes in methylation patterns were revealed with methylated DNA genome-wide sequencing analysis (n = 7) for FOG-1, RCOR-1, ZBTB7A and genes of the NuRD-complex components. Targeted pyrosequencing methodology (n = 28) revealed a strong inverse correlation between the degree of γ-globin gene (HBG2) promoter methylation and baseline HbF levels (p = 0.003, r = - 0.663). A potential epigenetic mechanism of HbF re-expression in azacytidine responders was enlightened by targeted methylation analysis, through hypomethylation of site -53 of HBG2 promoter (p = 0.039, r = - 0.504), which corresponds to MBD2-NuRD binding site, and to hypermethylation of the CpG326 island of ZBTB7A (p = 0.05, r = 0.482), a known HbF repressor. These changes were associated to blast cell clearance (p = 0.011, r = 0.480/p = 0.026, r = 0.427) and showed prognostic value for PFS (p = 0.037, HR = 1.14, CI 0.34-3.8).
Early HbF induction is featured as an accessible prognostic indicator for HMA treatment and the proposed potential epigenetic mechanism of HbF re-expression in azacytidine responders includes hypomethylation of the γ-globin gene promoter region and hypermethylation of the CpG326 island of ZBTB7A. The association of these methylation patterns with blast clearance and their prognostic value for PFS paves the way to discuss in-depth azacytidine epigenetic mechanism of action.
随着针对高危骨髓增生异常综合征患者的新治疗方案不断涌现，识别低甲基化药物（HMA）治疗的预后标志物并了解其延迟和短期反应的机制至关重要。早期胎儿血红蛋白（HbF）的诱导已被认为是地西他滨治疗患者的预后指标。尽管假设存在表观遗传机制，但应答患者的表观基因组尚未得到彻底研究。我们旨在阐明阿扎胞苷治疗患者的 HbF 动力学和预后价值，以及可能影响 HbF 再表达的表观遗传景观及其临床相关性。
通过高效液相色谱法（n=20）进行的系列 HbF 测量仅在应答者中显示出 HbF 的诱导（p=0.030）。此外，阿扎胞苷第一个周期后 HbF 的即刻增加对无进展生存期（PFS）具有预后价值（p=0.032，HR=0.19，CI 0.24-1.63）。通过对 FOG-1、RCOR-1、ZBTB7A 和 NuRD 复合物成分的基因进行甲基化 DNA 全基因组测序分析（n=7）揭示了甲基化模式的变化。通过靶向焦磷酸测序方法（n=28）发现，γ-珠蛋白基因（HBG2）启动子的甲基化程度与基线 HbF 水平之间存在强烈的负相关（p=0.003，r=−0.663）。通过靶向甲基化分析，揭示了阿扎胞苷应答者中 HbF 再表达的潜在表观遗传机制，即 HBG2 启动子-53 位点的低甲基化（p=0.039，r=−0.504），这与 MBD2-NuRD 结合位点相对应，以及 ZBTB7A 的 CpG326 岛的高甲基化（p=0.05，r=0.482），这是已知的 HbF 抑制剂。这些变化与原始细胞清除有关（p=0.011，r=0.480/p=0.026，r=0.427），并对 PFS 具有预后价值（p=0.037，HR=1.14，CI 0.34-3.8）。
早期 HbF 诱导是 HMA 治疗的一种可行的预后指标，阿扎胞苷应答者中 HbF 再表达的拟议潜在表观遗传机制包括γ-珠蛋白基因启动子区域的低甲基化和 ZBTB7A 的 CpG326 岛的高甲基化。这些甲基化模式与原始细胞清除的关联及其对 PFS 的预后价值为深入探讨阿扎胞苷的作用机制铺平了道路。
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