1. Conditional knockin of Dnmt3a R878H initiates acute myeloid leukemia with mTOR pathway involvement.
- Author
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Yu-Jun Dai, Yue-Ying Wang, Jin-Yan Huang, Li Xia, Xiao-Dong Shi, Jie Xu, Jing Lu, Xian-Bin Su, Ying Yang, Wei-Na Zhang, Pan-Pan Wang, Song-Fang Wu, Ting Huang, Jian-Qing Mi, Ze-Guang Han, Zhu Chen, and Sai-Juan Chen
- Subjects
ACUTE myeloid leukemia ,GENETIC mutation ,LABORATORY mice ,DNA methylation ,RNA sequencing ,PROGENITOR cells ,GENE expression - Abstract
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 Dnmt3aR878H/WT mice. [ABSTRACT FROM AUTHOR]- Published
- 2017
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