Study on the Immune Escape Mechanism of Acute Myeloid Leukemia With DNMT3A Mutation.
Study on the Immune Escape Mechanism of Acute Myeloid Leukemia With DNMT3A Mutation.
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DNMT3A突变的急性髓系白血病免疫逃逸机制研究
DOI：
10.3389/fimmu.2021.653030
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发表时间：
2021
影响因子：
7.3
通讯作者：
Li D
中科院分区：
文献类型：
--
作者：
Que Y;Li H;Lin L;Zhu X;Xiao M;Wang Y;Zhu L;Li D
DNA(胞嘧啶-5)-甲基转移酶3A(DNMT3A)突变的急性髓系白血病(AML)预后较差，但其确切机制尚不清楚。本研究旨在探讨DNMT3A突变AML的免疫逃逸机制。构建了DNMT3A基因敲除克隆和DNMT3A-R882H突变克隆。RNA-seq结果显示，在DNMT3A突变克隆中，转录因子和巨噬细胞炎症蛋白的表达显著下调。KEGG富集度和基因集富集度分析(GSEA)显示，炎症免疫相关通路中有大量基因富含，如Toll样受体信号通路。因此，我们将AML细胞与巨噬细胞共培养。DNMT3A突变的AML细胞在体内外均能减弱M1巨噬细胞的极化并抵抗其杀伤作用。在移植瘤中，实验组肿瘤体积明显大于对照组，且M2巨噬细胞比例明显高于对照组。共培养后，突变细胞中促炎症因子表达的增加明显低于对照组，而免疫抑制因子的表达差异无统计学意义。共培养上清液中，实验组炎症因子浓度明显低于对照组，免疫抑制因子浓度显著高于对照组。抵抗素显著促进急性髓系白血病细胞炎性蛋白的表达。解除DNMT3A突变的抑制作用，促进共培养巨噬细胞表型恢复，消除耐药性，调节免疫微环境。因此，抵抗素可作为DNMT3A突变AML患者的辅助药物。
DNA (cytosine-5)-methyltransferase 3A (DNMT3A)-mutated acute myeloid leukemia (AML) has a poor prognosis, but the exact mechanism is still unclear. Here, we aimed to explore the mechanism of immune escape in AML with DNMT3A mutation. We constructed a DNMT3A knockout clone and DNMT3A-R882H-mutated clones. RNA-seq results showed that transcription factors and macrophage inflammatory proteins were significantly downregulated in the DNMT3A mutant clones. KEGG enrichment and gene set enrichment analysis (GSEA) showed that a large number of genes were enriched in inflammatory immune-related pathways, such as the toll-like receptor signaling pathway. Therefore, we co-cultured AML cells with macrophages. The DNMT3A-mutated AML cells attenuated M1 macrophage polarization and resisted its killing effect in vitro and in vivo. In xenografts, the tumor volumes in the experimental group were significantly larger than those in the control group, and the proportion of M2 macrophages was significantly higher. After the co-culture, the increase in pro-inflammatory cytokine expression in the mutant cells was significantly lower than that in the control group, while that in immunosuppressive factors was not significantly different. In co-cultivated supernatants, the concentration of inflammatory factors in the experimental group was significantly lower than that in the control group, while that of immunosuppressive factors was significantly higher. Resistin significantly promoted the expression of inflammatory proteins in AML cells. It relieved the inhibitory effect of DNMT3A mutation, promoted the phenotypic recovery of the co-cultured macrophages, eliminated resistance, and regulated the immune microenvironment. Thus, resistin may serve as an ancillary drug for patients with DNMT3A-mutated AML.
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影响因子：
50.3
作者：
Russler-Germain DA;Spencer DH;Young MA;Lamprecht TL;Miller CA;Fulton R;Meyer MR;Erdmann-Gilmore P;Townsend RR;Wilson RK;Ley TJ
通讯作者：
Ley TJ
影响因子：
2.8
作者：
Schroder, Kate;Sweet, Matthew J.;Hume, David A.
通讯作者：
Hume, David A.
影响因子：
--
作者：
Ahmad, Rasheed;Shihab, Puthiyaveetil Kochumon;Behbehani, Kazem
通讯作者：
Behbehani, Kazem
DOI：
10.1056/nejmoa1005143
发表时间：
2010-12-16
期刊：
The New England journal of medicine
影响因子：
--
作者：
Ley TJ;Ding L;Walter MJ;McLellan MD;Lamprecht T;Larson DE;Kandoth C;Payton JE;Baty J;Welch J;Harris CC;Lichti CF;Townsend RR;Fulton RS;Dooling DJ;Koboldt DC;Schmidt H;Zhang Q;Osborne JR;Lin L;O'Laughlin M;McMichael JF;Delehaunty KD;McGrath SD;Fulton LA;Magrini VJ;Vickery TL;Hundal J;Cook LL;Conyers JJ;Swift GW;Reed JP;Alldredge PA;Wylie T;Walker J;Kalicki J;Watson MA;Heath S;Shannon WD;Varghese N;Nagarajan R;Westervelt P;Tomasson MH;Link DC;Graubert TA;DiPersio JF;Mardis ER;Wilson RK
通讯作者：
Wilson RK
影响因子：
20.3
作者：
Shaknovich, Rita;Cerchietti, Leandro;Melnick, Ari
通讯作者：
Melnick, Ari