Institute of Hematology and Blood Transfusion, U Nemocnice 1, Prague, Czech Republic.
Neoplasma. 2012;59(2):168-74. doi: 10.4149/neo_2012_022.
Epigenetic de novo methylation of CpG islands is an important event in malignant transformation. Two genes are frequently methylated: cyclin-dependent kinase inhibitor 2B (CDKN2B) and cyclin-dependent kinase inhibitor 2A (CDKN2A). In our study methylation of these genes was studied in 63 patients with myelodysplastic syndromes (MDS), 2 with myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and 13 with acute myeloid leukemia (AML). Five patients were monitored during 5-azacytidine treatment. Twenty-six healthy donors were tested in a control group. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) method with all associated techniques was used for detection. Aberrant methylation was present in the CDKN2A gene in 38% and in the CDKN2B gene in 77% of the patients in MDS group. The level of methylation was higher in the group of AML patients - 77% in CDKN2A gene and 100% in CDKN2B gene. In MDS patients, an aberrant methylation was associated with a tendency to disease progression towards more advanced forms according to the World Health Organization (WHO) classification and the International Prognostic Scoring System (IPSS). Significant differences in methylation level were observed between early and advanced forms of MDS in CDKN2B gene (P value < 0.05) but not for CDKN2A gene. The trend of methylation in patients treated with azacitidine was analyzed in CDKN2B gene and correlated with the course of the disease. Increased methylation was connected with disease progression. We concluded that the methylation level of CDKN2B gene might be used as a marker of leukemic transformation in MDS. Our study indicates the role of hypermethylation as an important event in the progression of MDS to AML.
CpG 岛的表观遗传从头甲基化是恶性转化中的一个重要事件。两个基因经常发生甲基化：细胞周期蛋白依赖性激酶抑制剂 2B（CDKN2B）和细胞周期蛋白依赖性激酶抑制剂 2A（CDKN2A）。在我们的研究中，对 63 例骨髓增生异常综合征（MDS）患者、2 例骨髓增生异常/骨髓增殖性肿瘤（MDS/MPN）和 13 例急性髓系白血病（AML）患者的这些基因进行了甲基化研究。对 5 例患者进行了 5-氮杂胞苷治疗监测。在对照组中检测了 26 名健康供体。使用带有所有相关技术的甲基化特异性多重连接依赖性探针扩增（MS-MLPA）方法进行检测。MDS 组中 38%的患者存在 CDKN2A 基因异常甲基化，77%的患者存在 CDKN2B 基因异常甲基化。AML 患者的甲基化水平更高-77%的 CDKN2A 基因和 100%的 CDKN2B 基因。在 MDS 患者中，异常甲基化与疾病向更高级形式（根据世界卫生组织（WHO）分类和国际预后评分系统（IPSS））进展的趋势相关。在 CDKN2B 基因中，早期和晚期 MDS 之间观察到甲基化水平的显著差异（P 值<0.05），但在 CDKN2A 基因中则没有。在 CDKN2B 基因中分析了接受阿扎胞苷治疗的患者的甲基化趋势，并与疾病过程相关。甲基化增加与疾病进展相关。我们得出结论，CDKN2B 基因的甲基化水平可能可作为 MDS 向白血病转化的标志物。我们的研究表明，超甲基化作为 MDS 向 AML 进展的一个重要事件的作用。
