Conditional knockin of Dnmt3a R878H initiates acute myeloid leukemia with mTOR pathway involvement

Abstract

<i>DNMT3A</i> is frequently mutated in acute myeloid leukemia (AML). To explore the features of human AML with the hotspot <i>DNMT3A</i> 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 <i>mTOR</i> 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.