Age-related epigenetic drift in the pathogenesis of MDS and AML.
Age-related epigenetic drift in the pathogenesis of MDS and AML.
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DOI：
10.1101/gr.157529.113
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发表时间：
2014-04
期刊：
影响因子：
7
通讯作者：
Issa JP
中科院分区：
文献类型：
--
作者：
Maegawa S;Gough SM;Watanabe-Okochi N;Lu Y;Zhang N;Castoro RJ;Estecio MR;Jelinek J;Liang S;Kitamura T;Aplan PD;Issa JP
骨髓增生异常综合征（MDS）是一种克隆性血液系统疾病，常进展为急性髓系白血病（AML）。其发病机制仍不清楚，但表观遗传修饰因子的突变很常见，且该疾病通常对DNA甲基化抑制剂有反应。我们分析了两种MDS/AML小鼠模型（NUP98 - HOXD13（NHD13）小鼠和RUNX1突变小鼠模型）骨髓和脾脏中的DNA甲基化情况。甲基化芯片分析显示，在NHD13 MDS中平均有512/3445（14.9%）个基因高甲基化，在RUNX1 MDS中有331（9.6%）个基因高甲基化。两种模型（2/3的NHD13小鼠和2/3的RUNX1小鼠）共有的基因中有32%在19个人类MDS样本中的至少两个样本中也高甲基化。对小鼠41个基因的详细分析显示，从年轻到年老的正常骨髓和脾脏，DNA甲基化逐渐漂移；到MDS时，我们检测到与年龄相关的甲基化加速；最后到AML，其DNA甲基化异常显著扩大。这些基因中的大多数在人类MDS和AML中表现出相似的模式。重复元件低甲基化在MDS中很少见，但在某些情况下标志着向AML的转变。我们的数据显示人类和小鼠MDS中异常DNA甲基化模式具有一致性，并表明从表观遗传学角度来看，MDS呈现出一种加速衰老的表型。
The myelodysplastic syndrome (MDS) is a clonal hematologic disorder that frequently evolves to acute myeloid leukemia (AML). Its pathogenesis remains unclear, but mutations in epigenetic modifiers are common and the disease often responds to DNA methylation inhibitors. We analyzed DNA methylation in the bone marrow and spleen in two mouse models of MDS/AML, the NUP98-HOXD13 (NHD13) mouse and the RUNX1 mutant mouse model. Methylation array analysis showed an average of 512/3445 (14.9%) genes hypermethylated in NHD13 MDS, and 331 (9.6%) genes hypermethylated in RUNX1 MDS. Thirty-two percent of genes in common between the two models (2/3 NHD13 mice and 2/3 RUNX1 mice) were also hypermethylated in at least two of 19 human MDS samples. Detailed analysis of 41 genes in mice showed progressive drift in DNA methylation from young to old normal bone marrow and spleen; to MDS, where we detected accelerated age-related methylation; and finally to AML, which markedly extends DNA methylation abnormalities. Most of these genes showed similar patterns in human MDS and AML. Repeat element hypomethylation was rare in MDS but marked the transition to AML in some cases. Our data show consistency in patterns of aberrant DNA methylation in human and mouse MDS and suggest that epigenetically, MDS displays an accelerated aging phenotype.
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全基因组甲基化谱揭示了人类衰老速度的定量观点。
影响因子：
16
作者：
Hannum, Gregory;Guinney, Justin;Zhao, Ling;Zhang, Li;Hughes, Guy;Sadda, SriniVas;Klotzle, Brandy;Bibikova, Marina;Fan, Jian-Bing;Gao, Yuan;Deconde, Rob;Chen, Menzies;Rajapakse, Indika;Friend, Stephen;Ideker, Trey;Zhang, Kang
通讯作者：
Zhang, Kang
DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
3.1
作者：
Aggerholm, A;Holm, MS;Hokland, P
通讯作者：
Hokland, P
影响因子：
11.2
作者：
Hahn MA;Hahn T;Lee DH;Esworthy RS;Kim BW;Riggs AD;Chu FF;Pfeifer GP
通讯作者：
Pfeifer GP