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Conditional knockin of Dnmt3a R878H initiates acute myeloid leukemia with mTOR pathway involvement
- Source :
- Proceedings of the National Academy of Sciences. 114:5237-5242
- Publication Year :
- 2017
- Publisher :
- Proceedings of the National Academy of Sciences, 2017.
-
Abstract
- Significance DNMT3A is a critical epigenetic modifier and tumor suppressor in the hematopoietic system. This gene is frequently mutated in hematopoietic malignancies, including acute myeloid leukemia (AML), with Dnmt3a R878H being the most common mutant. By using a conditional knockin approach, this study shows that Dnmt3a R878H is sufficient to initiate AML and recapitulate human leukemic features in mice. The leukemia-initiating cells are enriched in hematopoietic stem/progenitor cells. Through gene expression profiling, DNA methylation and histone modification analysis, and functional tests on important regulators for cell proliferation and differentiation in an animal model, this study has not only discovered mTOR pathway activation as a key player in the disease mechanism but also revealed the potential therapeutic effects of mTOR inhibition on DNMT3A mutation-related leukemia.
- Subjects :
- 0301 basic medicine
Myeloid
Cellular differentiation
Biology
DNA Methyltransferase 3A
Transcriptome
Mice
03 medical and health sciences
hemic and lymphatic diseases
medicine
Animals
DNA (Cytosine-5-)-Methyltransferases
Gene Knock-In Techniques
Progenitor cell
DNA Modification Methylases
PI3K/AKT/mTOR pathway
Multidisciplinary
Base Sequence
Gene Expression Profiling
TOR Serine-Threonine Kinases
Myeloid leukemia
Cell Differentiation
DNA Methylation
Biological Sciences
medicine.disease
Molecular biology
Disease Models, Animal
Leukemia, Myeloid, Acute
Leukemia
030104 developmental biology
medicine.anatomical_structure
Mutation
embryonic structures
DNA methylation
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 114
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....425d233aa7e68d725cef48261b615241