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Conditional knockin of Dnmt3a R878H initiates acute myeloid leukemia with mTOR pathway involvement
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.
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“Additionally, Dnmt3a deletion in hematopoietic stem cells induces leukemic transformation with accumulation of additional mutations in genes involved in regulating stem cell growth and survival, including cKit, Flt3, and Ras (14, 15).”
From Loss of Dnmt3a impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway (2023) · cites this paper as [14]
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mTORC1 controls the adaptive transition of quiescent stem cells from G0 to GAlert
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“In view of the gene transcriptional changes of a large number of pathways, including mTOR in BM cells of Dnmt3a mice and the previous finding that DNMT3A mutations could alter DNA methyltransferase activity (2, 10), we hypothesized that the disturbance in genomic methylation might play a role in causing the aberrant t…”
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Cited by
Clonal Hematopoiesis and Evolution to Hematopoietic Malignancies
Bowman, R. L., Busque, L., & Levine, R. L. (2018) · Cell stem cell · doi:10.1016/j.stem.2018.01.011 · Cited by 448
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Loss of Dnmt3a impairs hematopoietic homeostasis and myeloid cell skewing via the PI3Kinase pathway
Palam, L. R., Ramdas, B., Pickerell, K., Pasupuleti, S. K., Kanumuri, R., Cesarano, A., Szymanski, M., Selman, B., Dave, U. P., Sandusky, G., et al. (2023) · JCI Insight · doi:10.1172/jci.insight.163864 · Cited by 13
Metadata
- Authors
- Dai, Y.-J., Wang, Y.-Y., Huang, J.-Y., Xia, L., Shi, X.-D., Xu, J., Lu, J., Su, X.-B., Yang, Y., Zhang, W.-N., Wang, P.-P., Wu, S.-F., Huang, T., Mi, J.-Q., Han, Z.-G., Chen, Z., & Chen, S.-J.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-05
- Volume
- 114
- Issue
- 20
- Pages
- 5237-5242
- ISSN
- 0027-8424
- 1091-6490
- Cited by
- 78
- References
- 8
- Language
- en
- Funders
- National key basic research program of china (2013CB966800)
- Ministry of health grant (201202003)
- Mega-projects of scientific research for the 12th five-year plan (2013ZX09303302)
- National nature science foundation of china (81123005, 81222004, 81570151)
- Shanghai talent development fund (201458)
- Shanghai municipal education commission-gaofeng clinical medicine grant (20152507)
- Innovation foundation for doctoral students of shanghai jiaotong university school of medicine grant (BXJ201611)
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- Dai, Y.-J., Wang, Y.-Y., Huang, J.-Y., Xia, L., Shi, X.-D., Xu, J., Lu, J., Su, X.-B., Yang, Y., Zhang, W.-N., Wang, P.-P., Wu, S.-F., Huang, T., Mi, J.-Q., Han, Z.-G., Chen, Z., & Chen, S.-J. (2017). Conditional knockin of Dnmt3a R878H initiates acute myeloid leukemia with mTOR pathway involvement. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1703476114
