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PMID: 21040901 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

mTOR activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after Pten deletion.

Cell stem cell ·Vol. 7 ·No. 5 ·2010-11-05 ·Pages 593-605

Lee JY, Nakada D, Yilmaz OH, Tothova Z, Joseph NM, Lim MS, Gilliland DG, Morrison SJ

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 p16(Ink4a) and p53 in HSCs, and p19(Arf) 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. p19(Arf) 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.

MeSH Terms
Animals Cells, Cultured Down-Regulation Flow Cytometry Gene Deletion Gene Expression Regulation, Neoplastic Genes, Tumor Suppressor/physiology Hematopoietic Stem Cells/cytology Leukemia/prevention & control Mice Mice, Inbred C57BL PTEN Phosphohydrolase/genetics TOR Serine-Threonine Kinases/genetics,metabolism
Chemicals
TOR Serine-Threonine Kinases PTEN Phosphohydrolase PTEN protein, human
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Lee Jae Y
Howard Hughes Medical Institute, Center for Stem Cell Biology, Life Sciences Institute, and Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Nakada Daisuke
Yilmaz Omer H
Tothova Zuzana
Joseph Nancy M
Lim Megan S
Gilliland D Gary
Morrison Sean J
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Article Info
Journal
Cell stem cell
Abbr.
Cell Stem Cell
ISSN
1875-9777
DOI
10.1016/j.stem.2010.09.015
Published
2010-11-05
Pages
593-605
Language
English
Region
United States
NLM ID
101311472
PMCID
PMC2995996
Subset
IM
Grants
Howard Hughes Medical Institute · United States
NCI NIH HHS · P30 CA046592 · United States
NCI NIH HHS · CA46592 · United States
External Links
PubMed source DOI: 10.1016/j.stem.2010.09.015 PMC Full Text View journal details
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