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Cooperation of Dnmt3a R878H with Nras G12D promotes leukemogenesis in knock-in mice: a pilot study
- Source :
- BMC Cancer, BMC Cancer, Vol 19, Iss 1, Pp 1-11 (2019)
- Publication Year :
- 2018
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Neuroblastoma RAS viral oncogene homolog
Cancer Research
Transcription, Genetic
Carcinogenesis
Mutant
Apoptosis
Pilot Projects
DNA Methyltransferase 3A
Mice
0302 clinical medicine
DNA (Cytosine-5-)-Methyltransferases
Gene Knock-In Techniques
RNA-Seq
medicine.diagnostic_test
Myeloid leukemia
Cell Differentiation
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Gene Expression Regulation, Neoplastic
Haematopoiesis
Leukemia, Myeloid, Acute
Phenotype
Oncology
030220 oncology & carcinogenesis
embryonic structures
Disease Progression
Research Article
Longevity
Mice, Transgenic
Biology
lcsh:RC254-282
Nras G12D
Flow cytometry
Proto-Oncogene Proteins c-myc
03 medical and health sciences
Western blot
Gene knockin
Genetics
medicine
Animals
Gene
Monomeric GTP-Binding Proteins
Myc activation
Acute myeloid leukemia
Mice, Inbred C57BL
Disease Models, Animal
030104 developmental biology
Mutation
Cancer research
DNMT3A mutation
Subjects
Details
- ISSN :
- 14712407
- Volume :
- 19
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- BMC cancer
- Accession number :
- edsair.doi.dedup.....eddc7490155ddcfa3764c380c4c62c6e