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首页> 外文期刊>Nature cancer. >Hotspot DNMT3A mutations in clonal hematopoiesis and acute myeloid leukemia sensitize cells to azacytidine via viral mimicry response
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Hotspot DNMT3A mutations in clonal hematopoiesis and acute myeloid leukemia sensitize cells to azacytidine via viral mimicry response

机译：热点DNMT3A突变克隆造血作用使敏感细胞和急性髓系白血病azacytidine通过病毒拟态的回应

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摘要

Somatic mutations in DNA methyltransferase 3A (DNMT3A) are among the most frequent alterations in clonal hematopoiesis (CH) and acute myeloid leukemia (AMD, with a hotspot in exon 23 at arginine 882 (DNMT3A~(R882)). Here, we demonstrate that DNMT3A~(R882H)-dependent CH and AML cells are specifically susceptible to the hypomethylating agent azacytidine (AZA). Addition of AZA to chemotherapy prolonged AML survival solely in individuals with DNMT3A~(R882) mutations, suggesting its potential as a predictive marker for AZA response. AML and CH mouse models confirmed AZA susceptibility specifically in DNMT3A~(R882H)-expressing cells. Hematopoietic stem cells (HSCs) and progenitor cells expressing DNMT3A~(R882H) exhibited cell autonomous viral mimicry response as a result of focal DNA hypomethylation at retrotransposon sequences. Administration of AZA boosted hypomethylation of retrotransposons specifically in DAMWT3A~(R882H)-expressing cells and maintained elevated levels of canonical interferon-stimulated genes (ISGs), thus leading to suppressed protein translation and increased apoptosis.
机译：体细胞突变DNA甲基转移酶3(DNMT3A)是最频繁的改变在克隆造血作用(CH)和急性骨髓白血病(AMD,热点外显子23精氨酸882 (DNMT3A ~ (R882))。证明DNMT3A ~ (R882H)端依赖CH和AML细胞特别容易hypomethylating代理azacytidine(阿扎)。阿扎的化疗延长AML的生存只在个人DNMT3A ~ (R882)突变,暗示其潜在的作为预测的标志阿扎的回应。小鼠模型证实了阿扎易感性特别是在DNMT3A ~ (R882H)表达细胞。造血干细胞(hsc)和祖细胞表达DNMT3A ~ (R882H)表现出细胞自治病毒模仿响应的结果焦DNA hypomethylation逆转录转座子序列。hypomethylation反转位子活动的具体在DAMWT3A ~ (R882H)表达细胞保持高水平的标准干扰素刺激基因(isg),从而领先抑制蛋白质翻译和增加细胞凋亡。

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