%0 Journal Article
%T Cooperation of Dnmt3a R878H with Nras G12D promotes leukemogenesis in knock-in mice: a pilot study.
%A Shi X
%A Yang Y
%A Shang S
%A Wu S
%A Zhang W
%A Peng L
%A Huang T
%A Zhang R
%A Ren R
%A Mi J
%A Wang Y
%J BMC Cancer
%V 19
%N 1
%D Nov 2019 8
%M 31703632
%F 4.638
%R 10.1186/s12885-019-6207-y
%X <B>BACKGROUND: </B>DNMT3A R882H, a frequent mutation in acute myeloid leukemia (AML), plays a critical role in malignant hematopoiesis. Recent findings suggest that DNMT3A mutant acts as a founder mutation and requires additional genetic events to induce full-blown AML. Here, we investigated the cooperation of mutant DNMT3A and NRAS in leukemogenesis by generating a double knock-in (DKI) mouse model harboring both Dnmt3a R878H and Nras G12D mutations.<BR><B>METHODS: </B>DKI mice with both Dnmt3a R878H and Nras G12D mutations were generated by crossing Dnmt3a R878H knock-in (KI) mice and Nras G12D KI mice. Routine blood test, flow cytometry analysis and morphological analysis were performed to determine disease phenotype. RNA-sequencing (RNA-seq), RT-PCR and Western blot were carried out to reveal the molecular mechanism.<BR><B>RESULTS: </B>The DKI mice developed a more aggressive AML with a significantly shortened lifespan and higher percentage of blast cells compared with KI mice expressing Dnmt3a or Nras mutation alone. RNA-seq analysis showed that Dnmt3a and Nras mutations collaboratively caused abnormal expression of a series of genes related to differentiation arrest and growth advantage. Myc transcription factor and its target genes related to proliferation and apoptosis were up-regulated, thus contributing to promote the process of leukemogenesis.<BR><B>CONCLUSIONS: </B>This study showed that cooperation of DNMT3A mutation and NRAS mutation could promote the onset of AML by synergistically disturbing the transcriptional profiling with Myc pathway involvement in DKI mice.