Hotspot DNMT3A mutations in clonal hematopoiesis and acute myeloid leukemia sensitize cells to azacytidine via viral mimicry response
Hotspot DNMT3A mutations in clonal hematopoiesis and acute myeloid leukemia sensitize cells to azacytidine via viral mimicry response
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DOI：
10.1038/s43018-021-00213-9
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发表时间：
2021-05-01
期刊：
影响因子：
22.7
通讯作者：
Muller-Tidow，Carsten
中科院分区：
文献类型：
--
作者：
Scheller，Marina;Ludwig，Anne Kathrin;Muller-Tidow，Carsten
DNA甲基转移酶3A （DNMT3A）的体细胞突变是克隆造血（CH）和急性髓系白血病（AML）中最常见的突变之一，其热点位于23外显子精氨酸882 （DNMT3AR882）。在这里，我们证明了dnmt3ar882h依赖性的CH和AML细胞对低甲基化剂阿扎胞苷（AZA）特别敏感。仅在dnmt3ar882突变个体中，在化疗中加入AZA可延长AML生存期，这表明其作为AZA反应的预测标志物的潜力。AML和CH小鼠模型证实了特异性表达indnmt3ar882h的细胞对AZA的敏感性。表达dnmt3ar882h的造血干细胞和祖细胞表现出细胞自主病毒模仿反应，这是逆转录转座子序列局部DNA低甲基化的结果。给药AZA促进了逆转录转座子特异性表达indnmt3ar882h的细胞的低甲基化，并维持了典型干扰素刺激基因（ISGs）水平的升高，从而导致蛋白质翻译抑制和细胞凋亡增加。
Somatic mutations in DNA methyltransferase 3A (DNMT3A) are among the most frequent alterations in clonal hematopoiesis (CH) and acute myeloid leukemia (AML), with a hotspot in exon 23 at arginine 882 (DNMT3AR882). Here, we demonstrate thatDNMT3AR882H-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 withDNMT3AR882mutations, suggesting its potential as a predictive marker for AZA response. AML and CH mouse models confirmed AZA susceptibility specifically inDNMT3AR882H-expressing cells. Hematopoietic stem cells (HSCs) and progenitor cells expressingDNMT3AR882Hexhibited cell autonomous viral mimicry response as a result of focal DNA hypomethylation at retrotransposon sequences. Administration of AZA boosted hypomethylation of retrotransposons specifically inDNMT3AR882H-expressing cells and maintained elevated levels of canonical interferon-stimulated genes (ISGs), thus leading to suppressed protein translation and increased apoptosis.