MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation
MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation
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DOI：
10.1182/blood-2009-01-200519
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发表时间：
2009-10-15
期刊：
影响因子：
20.3
通讯作者：
Melnick, Ari
中科院分区：
文献类型：
--
作者：
Figueroa, Maria E.;Skrabanek, Lucy;Melnick, Ari
越来越多的证据表明，基因异常甲基化发生在骨髓恶性肿瘤中，并可能导致其发病。这些疾病中的几种，如骨髓增生异常综合征（MDS），对DNA甲基转移酶抑制剂有反应。为了确定这种肿瘤中启动子高甲基化的程度，我们比较了MDS和继发性急性髓性白血病（AML）患者中14000个启动子的DNA甲基化分布，这些患者参加了5-氮杂胞苷和组蛋白脱乙酰酶抑制剂恩替诺特与新生AML患者和正常CD 34（+）骨髓细胞的I期试验。MDS和继发性AML患者比正常的CD 34（+）骨髓细胞或原发性AML原始细胞显示出更广泛的异常DNA甲基化，涉及数千个基因。MDS和继发性AML中的异常甲基化倾向于影响特定的染色体区域，更频繁地发生在β-贫基因中，并且包括参与WNT和MAPK信号通路的基因的显著参与。还在第一个治疗周期后第15天和第29天测量DNA甲基化。DNA甲基化在第15天以均匀的方式在整个基因组中逆转，并且这种作用持续到第29天，即使没有连续给予研究药物。该试验在www.clinicaltrials.gov上注册为J 0443。（血。2009;114：3448-3458）
Increasing evidence shows aberrant hypermethylation of genes occurring in and potentially contributing to pathogenesis of myeloid malignancies. Several of these diseases, such as myelodysplastic syndromes (MDSs), are responsive to DNA methyltransferase inhibitors. To determine the extent of promoter hypermethylation in such tumors, we compared the distribution of DNA methylation of 14 000 promoters in MDS and secondary acute myeloid leukemia (AML) patients enrolled in a phase 1 trial of 5-azacytidine and the histone deacetylase inhibitor entinostat against de novo AML patients and normal CD34(+) bone marrow cells. The MDS and secondary AML patients displayed more extensive aberrant DNA methylation involving thousands of genes than did the normal CD34(+) bone marrow cells or de novo AML blasts. Aberrant methylation in MDS and secondary AML tended to affect particular chromosomal regions, occurred more frequently in Alu-poor genes, and included prominent involvement of genes involved in the WNT and MAPK signaling pathways. DNA methylation was also measured at days 15 and 29 after the first treatment cycle. DNA methylation was reversed at day 15 in a uniform manner throughout the genome, and this effect persisted through day 29, even without continuous administration of the study drugs. This trial was registered at www.clinicaltrials.gov as J0443. (Blood. 2009;114:3448-3458)