| First Author | Shi X | Year | 2019 |
| Journal | BMC Cancer | Volume | 19 |
| Issue | 1 | Pages | 1072 |
| PubMed ID | 31703632 | Mgi Jnum | J:290465 |
| Mgi Id | MGI:6435385 | Doi | 10.1186/s12885-019-6207-y |
| Citation | Shi X, et al. (2019) Cooperation of Dnmt3a R878H with Nras G12D promotes leukemogenesis in knock-in mice: a pilot study. BMC Cancer 19(1):1072 |
| abstractText | BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. |
