The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index.
mTOR Activation Induces Tumor Suppressors that Inhibit Leukemogenesis and Deplete Hematopoietic Stem Cells after Pten Deletion
Open accessAbstract
SUMMARY Pten deficiency depletes hematopoietic stem cells (HSCs) but expands leukemia-initiating cells and the mTOR inhibitor, rapamycin, blocks these effects. Understanding the opposite effects of mTOR activation on HSCs versus leukemia-initiating cells could improve anti-leukemia therapies. We found that the depletion of Pten-deficient HSCs was not caused by oxidative stress and could not be blocked by N-acetyl-cysteine. Instead, Pten deletion induced, and rapamycin attenuated, the expression of p16Ink4a and p53 in HSCs, and p19Arf and p53 in other hematopoietic cells. p53 suppressed leukemogenesis and promoted HSC depletion after Pten deletion. p16Ink4a also promoted HSC depletion but had a limited role suppressing leukemogenesis. p19Arf strongly suppressed leukemogenesis but did not deplete HSCs. Secondary mutations attenuated this tumor suppressor response in some leukemias that arose after Pten deletion. mTOR activation therefore depletes HSCs by a tumor suppressor response that is attenuated by secondary mutations in leukemogenic clones.
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Citations
Cites
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,218 · cited 3×
“The mechanisms behind p16Ink4a and p53 activation in response to Ras activation also remain unknown (Serrano et al., 1997).”
BackgroundTSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
Inoki, K., Li, Y., Zhu, T., Wu, J., & Guan, K.-L. (2002) · Nature Cell Biology · doi:10.1038/ncb839 · Cited by 3,083
Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis
Chen, Z., Trotman, L. C., Shaffer, D., Lin, H.-K., Dotan, Z. A., Niki, M., Koutcher, J. A., Scher, H. I., Ludwig, T., Gerald, W., et al. (2005) · Nature · doi:10.1038/nature03918 · Cited by 1,993
Tumor Suppression at the Mouse INK4a Locus Mediated by the Alternative Reading Frame Product p19
Kamijo, T., Zindy, F., Roussel, M. F., Quelle, D. E., Downing, J. R., Ashmun, R. A., Grosveld, G., & Sherr, C. J. (1997) · Cell · doi:10.1016/s0092-8674(00)80452-3 · Cited by 1,566
FoxOs Are Critical Mediators of Hematopoietic Stem Cell Resistance to Physiologic Oxidative Stress
Tothova, Z., Kollipara, R., Huntly, B. J., Lee, B. H., Castrillon, D. H., Cullen, D. E., McDowell, E. P., Lazo-Kallanian, S., Williams, I. R., Sears, C., et al. (2007) · Cell · doi:10.1016/j.cell.2007.01.003 · Cited by 1,562
Self-citationReactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells
Ito, K., Hirao, A., Arai, F., Takubo, K., Matsuoka, S., Miyamoto, K., Ohmura, M., Naka, K., Hosokawa, K., Ikeda, Y., et al. (2006) · Nature Medicine · doi:10.1038/nm1388 · Cited by 1,362
Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization
Zindy, F., Eischen, C. M., Randle, D. H., Kamijo, T., Cleveland, J. L., Sherr, C. J., & Roussel, M. F. (1998) · Genes & Development · doi:10.1101/gad.12.15.2424 · Cited by 1,245
Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells
Ito, K., Hirao, A., Arai, F., Matsuoka, S., Takubo, K., Hamaguchi, I., Nomiyama, K., Hosokawa, K., Sakurada, K., Nakagata, N., et al. (2004) · Nature · doi:10.1038/nature02989 · Cited by 1,175 · cited 16×
“We were unable to detect FoxO3a inactivation or a significant increase in ROS levels in HSCs after Pten deletion.”
BackgroundInfluentialLoss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis
Sharpless, N. E., Bardeesy, N., Lee, K.-H., Carrasco, D., Castrillon, D. H., Aguirre, A. J., Wu, E. A., Horner, J. W., & DePinho, R. A. (2001) · Nature · doi:10.1038/35092592 · Cited by 848
PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention
Zhang, J., Grindley, J. C., Yin, T., Jayasinghe, S., He, X. C., Ross, J. T., Haug, J. S., Rupp, D., Porter-Westpfahl, K. S., Wiedemann, L. M., et al. (2006) · Nature · doi:10.1038/nature04747 · Cited by 817
Cited by
The functions and regulation of the PTEN tumour suppressor
Song, M. S., Salmena, L., & Pandolfi, P. P. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3330 · Cited by 1,926
Zhou, B. O., Yue, R., Murphy, M. M., Peyer, J. G., & Morrison, S. J. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.06.008 · Cited by 1,381
“PTEN Regulates Quiescence, Maintenance, and Differentiation of LepR Cells Pten is cell-autonomously required for the maintenance of HSCs (Kalaitzidis et al., 2012; Lee et al., 2010; Magee et al., 2012; Yilmaz et al., 2006; Zhang et al., 2006) and neural stem cells (Bonaguidi et al.”
InfluentialSelf-citationMetabolic 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
The functions and regulation of the PTEN tumour suppressor: new modes and prospects
Lee, Y.-R., Chen, M., & Pandolfi, P. P. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0015-0 · Cited by 917
Metabolic Regulation of Hematopoietic Stem Cells in the Hypoxic Niche
Suda, T., Takubo, K., & Semenza, G. L. (2011) · Cell Stem Cell · doi:10.1016/j.stem.2011.09.010 · Cited by 844
Metadata
- Authors
- Lee, J. Y., Nakada, D., Yilmaz, O. H., Tothova, Z., Joseph, N. M., Lim, M. S., Gilliland, D. G., & Morrison, S. J.
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2010-11
- Volume
- 7
- Issue
- 5
- Pages
- 593-605
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W2091273754
- Cited by
- 185
- References
- 13
- FWCI
- 10.77
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Lee, J. Y., Nakada, D., Yilmaz, O. H., Tothova, Z., Joseph, N. M., Lim, M. S., Gilliland, D. G., & Morrison, S. J. (2010). mTOR Activation Induces Tumor Suppressors that Inhibit Leukemogenesis and Deplete Hematopoietic Stem Cells after Pten Deletion. Cell Stem Cell. https://doi.org/10.1016/j.stem.2010.09.015
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