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标题：Conditional knockin of Dnmt3a R878H initiates acute myeloid leukemia with mTOR pathway involvement
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作者：Yu-Jun Dai ; Yue-Ying Wang ; Jin-Yan Huang 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：20
页码：5237-5242
DOI：10.1073/pnas.1703476114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：DNMT3A is frequently mutated in acute myeloid leukemia (AML). To explore the features of human AML with the hotspot DNMT3A R882H mutation, we generated Dnmt3a R878H conditional knockin mice, which developed AML with enlarged Lin⁻Sca1⁺cKit⁺ cell compartments. The transcriptome and DNA methylation profiling of bulk leukemic cells and the single-cell RNA sequencing of leukemic stem/progenitor cells revealed significant changes in gene expression and epigenetic regulatory patterns that cause differentiation arrest and growth advantage. Consistent with leukemic cell accumulation in G₂/M phase, CDK1 was up-regulated due to mTOR activation associated with DNA hypomethylation. Overexpressed CDK1-mediated EZH2 phosphorylation resulted in an abnormal trimethylation of H3K27 profile. The mTOR inhibitor rapamycin elicited a significant therapeutic response in Dnmt3a^R878H/WT mice.
关键词：Dnmt3a R878H mutation ; conditional knockin mice ; single-cell RNA-seq ; leukemia ; mTOR inhibitor