State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
Proc Natl Acad Sci U S A. 2017 May 16;114(20):5237-5242. doi: 10.1073/pnas.1703476114. Epub 2017 May 1.
is frequently mutated in acute myeloid leukemia (AML). To explore the features of human AML with the hotspot R882H mutation, we generated Dnmt3a R878H conditional knockin mice, which developed AML with enlarged LinSca1cKit 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 G/M phase, CDK1 was up-regulated due to 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 mice.
在急性髓系白血病（AML）中经常发生突变。为了探索具有热点 R882H 突变的人类 AML 的特征，我们生成了 Dnmt3a R878H 条件性敲入小鼠，其发展为具有扩大的 LinSca1cKit 细胞区室的 AML。批量白血病细胞的转录组和 DNA 甲基化谱分析以及白血病干细胞/祖细胞的单细胞 RNA 测序揭示了导致分化阻滞和生长优势的基因表达和表观遗传调控模式的显著变化。与 G/M 期白血病细胞积累一致，由于与 DNA 低甲基化相关的激活，CDK1 上调。过表达的 CDK1 介导的 EZH2 磷酸化导致 H3K27 异常三甲基化。mTOR 抑制剂雷帕霉素在 Dnmt3a 小鼠中引起了显著的治疗反应。
