Epigenetic Identity in AML Depends on Disruption of Nonpromoter Regulatory Elements and Is Affected by Antagonistic Effects of Mutations in Epigenetic Modifiers.
Epigenetic Identity in AML Depends on Disruption of Nonpromoter Regulatory Elements and Is Affected by Antagonistic Effects of Mutations in Epigenetic Modifiers.
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DOI：
10.1158/2159-8290.cd-16-1032
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发表时间：
2017-08
期刊：
影响因子：
28.2
通讯作者：
Figueroa ME
中科院分区：
文献类型：
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作者：
Glass JL;Hassane D;Wouters BJ;Kunimoto H;Avellino R;Garrett-Bakelman FE;Guryanova OA;Bowman R;Redlich S;Intlekofer AM;Meydan C;Qin T;Fall M;Alonso A;Guzman ML;Valk PJM;Thompson CB;Levine R;Elemento O;Delwel R;Melnick A;Figueroa ME
我们对遗传多样性AML患者进行了胞嘧啶甲基化测序，发现白血病DNA甲基化模式主要由非启动子调控元件和CpG序列驱动。增强子表现出更强的差异甲基化比启动子，主要是低甲基化。具有显性高甲基化的AML表现出更大的启动子表观遗传破坏，而具有显性低甲基化的AML表现出更大的远端和内含子区域破坏。IDH和DNMT 3A的突变对表观基因组具有相反和相互排斥的影响。值得注意的是，两种突变的共同发生导致表观遗传拮抗作用，其中仅受任一突变影响的大多数CpG在双突变AML中不再受影响。重要的是，这种表观遗传拮抗作用先于恶性转化，并且可以在来自Idh 2 R140 Q或Dnmt 3aR 882 H单突变小鼠和Idh 2 R140 Q/Dnmt 3aR 882 H双突变小鼠的白血病前LSK细胞中观察到。值得注意的是，与具有任一单突变的AML相比，IDH/DNMT 3A双突变AML表现出RAS信号传导特征的上调，并显示出对MEK离体抑制的独特敏感性。
We performed cytosine methylation sequencing on genetically diverse AML patients and found leukemic DNA methylation patterning is primarily driven by non-promoter regulatory elements and CpG shores. Enhancers displayed stronger differential methylation than promoters, consisting predominantly of hypomethylation. AMLs with dominant hypermethylation featured greater epigenetic disruption of promoters, while those with dominant hypomethylation displayed greater disruption of distal and intronic regions. Mutations in IDH and DNMT3A had opposing and mutually exclusive effects on the epigenome. Notably, co-occurrence of both mutations resulted in epigenetic antagonism, with most CpGs affected by either mutation alone no longer affected in double mutant AMLs. Importantly, this epigenetic antagonism precedes malignant transformation and can be observed in pre-leukemic LSK cells from Idh2R140Q or Dnmt3aR882H single and, Idh2R140Q/Dnmt3aR882H double mutant mice. Notably, IDH/DNMT3A double mutant AMLs manifested upregulation of RAS signaling signature and displayed unique sensitivity to MEK inhibition ex vivo as compared to AMLs with either single mutation.