The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.
Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice
Open accessAbstract
Human cancers, including acute myeloid leukemia (AML), commonly display constitutive phosphoinositide 3-kinase (PI3K) AKT signaling. However, the exact role of AKT activation in leukemia and its effects on hematopoietic stem cells (HSCs) are poorly understood. Several members of the PI3K pathway, phosphatase and tensin homolog (Pten), the forkhead box, subgroup O (FOXO) transcription factors, and TSC1, have demonstrated functions in normal and leukemic stem cells but are rarely mutated in leukemia. We developed an activated allele of AKT1 that models increased signaling in normal and leukemic stem cells. In our murine bone marrow transplantation model using a myristoylated AKT1 (myr-AKT), recipients develop myeloproliferative disease, T-cell lymphoma, or AML. Analysis of the HSCs in myr-AKT mice reveals transient expansion and increased cycling, associated with impaired engraftment. myr-AKT–expressing bone marrow cells are unable to form cobblestones in long-term cocultures. Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) rescues cobblestone formation in myr-AKT–expressing bone marrow cells and increases the survival of myr-AKT mice. This study demonstrates that enhanced AKT activation is an important mechanism of transformation in AML and that HSCs are highly sensitive to excess AKT/mTOR signaling.
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Cites
AKT/PKB signaling: navigating downstream
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FoxOs Are Critical Mediators of Hematopoietic Stem Cell Resistance to Physiologic Oxidative Stress
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PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention
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FoxO Transcription Factors and Stem Cell Homeostasis: Insights from the Hematopoietic System
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Song, M. S., Salmena, L., & Pandolfi, P. P. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3330 · Cited by 1,926
Metabolic requirements for the maintenance of self-renewing stem cells
Ito, K., & Suda, T. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3772 · Cited by 1,014
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Suda, T., Takubo, K., & Semenza, G. L. (2011) · Cell Stem Cell · doi:10.1016/j.stem.2011.09.010 · Cited by 844
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Mortensen, M., Soilleux, E. J., Djordjevic, G., Tripp, R., Lutteropp, M., Sadighi-Akha, E., Stranks, A. J., Glanville, J., Knight, S., W. Jacobsen, S.-E., et al. (2011) · Journal of Experimental Medicine · doi:10.1084/jem.20101145 · Cited by 657
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Kurek, K. C., Luks, V. L., Ayturk, U. M., Alomari, A. I., Fishman, S. J., Spencer, S. A., Mulliken, J. B., Bowen, M. E., Yamamoto, G. L., Kozakewich, H. P. W., et al. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2012.05.006 · Cited by 532
Metadata
- Authors
- Kharas, M. G., Okabe, R., Ganis, J. J., Gozo, M., Khandan, T., Paktinat, M., Gilliland, D. G., & Gritsman, K.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2010-02-18
- Volume
- 115
- Issue
- 7
- Pages
- 1406-1415
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2068604152
- Cited by
- 272
- References
- 6
- FWCI
- 11.69
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Kharas, M. G., Okabe, R., Ganis, J. J., Gozo, M., Khandan, T., Paktinat, M., Gilliland, D. G., & Gritsman, K. (2010). Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice. Blood. https://doi.org/10.1182/blood-2009-06-229443
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