@article{744214100ac347d3921e945b7fb7eb1f,
title = "MTOR activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after pten deletion",
abstract = "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 antileukemia 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. p16 Ink4a 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.",
author = "Lee, {Jae Y.} and Daisuke Nakada and Yilmaz, {Omer H.} and Zuzana Tothova and Joseph, {Nancy M.} and Lim, {Megan S.} and Gilliland, {D. Gary} and Morrison, {Sean J.}",
note = "Funding Information: This work was supported by the Howard Hughes Medical Institute. J.Y.L. was supported by predoctoral fellowships from the University of Michigan (UM) Biology of Aging Training Grant and the Medical Scientist Training Program. D.N. was supported by a postdoctoral fellowship from the Japan Society for the Promotion of Science. Flow cytometry was partially supported by the UM-Comprehensive Cancer NIH CA46592. Thanks to David Adams and Martin White for flow cytometry. Thanks to Chris Mountford and Sara Grove for mouse colony management and to Michael Smith and Mayya Malakh for help with genotyping. J.Y.L. and D.N. performed all experiments and participated in the design and interpretation of experiments. O.H.Y. initiated the project and generated the compound mutant mice. M.S.L. analyzed mouse pathology with help from J.Y.L. Z.T. and D.G.G. participated in the conception and interpretation of experiments. S.J.M. participated in the design and interpretation of Pten experiments and wrote the paper with J.Y.L. and D.N. ",
year = "2010",
month = nov,
day = "5",
doi = "10.1016/j.stem.2010.09.015",
language = "English (US)",
volume = "7",
pages = "593--605",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "5",
}