Department of Haematology, Huashan Hospital of Fudan University, 12 Wulumuqi Road Central, 200040 Shanghai, China.
Leuk Res. 2010 May;34(5):598-604. doi: 10.1016/j.leukres.2009.09.031. Epub 2009 Oct 23.
Epigenetic gene silencing due to promoter methylation is observed in human cancers like acute myeloid leukemia (AML). Little is known about aberrant methylation in myelodysplastic syndrome (MDS), a heterogeneous clonal stem cell disorder with a approximately 30% risk of transformation into secondary AML. Recent evidence demonstrated that ID4, a negative regulator of transcription, may act as a tumor-suppressor gene. To clarify the role of ID4 in MDS, we employed methylation-specific PCR (MSP) to examine the methylation status of ID4 in 144 adult de novo MDS patients. We found that ID4 methylation was present in 35.4% (n=51) of these MDS patients and methylaiton was correlated significantly with World Health Organization (WHO) subtypes and International Prognostic Scoring System (IPSS) risk groups. Patients with advanced stages of WHO subtypes (45.8% vs. 21.3%, P=0.002) and higher risk IPSS subgroups (45.7% vs. 26.0%, P=0.014) exhibited a significantly higher frequency of ID4 methylation. The median survival of patients with ID4 methylation was shorter than patients without ID4 methylation (12.2 months vs. 26.9 months, P=0.005). Multivariate analysis indicated that ID4 methylation status was the independent factor that impacted leukemia-free survival (LFS). Disease in patients with ID4 methylation progressed more rapidly than those without ID4 methylation (P=0.047, HR=2.11). Our results suggest that ID4 may be a therapeutic target in MDS.
表观遗传基因沉默由于启动子甲基化在人类癌症中观察到，如急性髓细胞性白血病（AML）。在骨髓增生异常综合征（MDS）中，异常甲基化知之甚少，MDS 是一种异质性克隆干细胞疾病，大约有 30%的风险转化为继发性 AML。最近的证据表明，转录的负调节剂 ID4 可能作为肿瘤抑制基因。为了阐明 ID4 在 MDS 中的作用，我们采用甲基化特异性 PCR（MSP）检测 144 例成人新发 MDS 患者 ID4 的甲基化状态。我们发现 ID4 甲基化存在于 35.4%（n=51）的这些 MDS 患者中，并且甲基化与世界卫生组织（WHO）亚型和国际预后评分系统（IPSS）风险组显著相关。WHO 亚型晚期阶段（45.8%比 21.3%，P=0.002）和更高风险 IPSS 亚组（45.7%比 26.0%，P=0.014）的患者 ID4 甲基化频率显著更高。ID4 甲基化患者的中位生存时间短于无 ID4 甲基化患者（12.2 个月比 26.9 个月，P=0.005）。多变量分析表明，ID4 甲基化状态是影响无白血病生存（LFS）的独立因素。ID4 甲基化患者的疾病进展速度快于无 ID4 甲基化患者（P=0.047，HR=2.11）。我们的结果表明，ID4 可能是 MDS 的治疗靶点。
