MTOR activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after pten deletion

Jae Y. Lee, Daisuke Nakada, Omer H. Yilmaz, Zuzana Tothova, Nancy M. Joseph, Megan S. Lim, D. Gary Gilliland, Sean J. Morrison

Research output: Contribution to journalArticle

132 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)593-605
Number of pages13
JournalCell Stem Cell
Volume7
Issue number5
DOIs
StatePublished - Nov 5 2010

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Hematopoietic Stem Cells
Neoplasms
Leukemia
Sirolimus
Mutation
Cysteine
Oxidative Stress
Clone Cells

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine
  • Genetics

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MTOR activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after pten deletion. / Lee, Jae Y.; Nakada, Daisuke; Yilmaz, Omer H.; Tothova, Zuzana; Joseph, Nancy M.; Lim, Megan S.; Gilliland, D. Gary; Morrison, Sean J.

In: Cell Stem Cell, Vol. 7, No. 5, 05.11.2010, p. 593-605.

Research output: Contribution to journalArticle

Lee, Jae Y. ; Nakada, Daisuke ; Yilmaz, Omer H. ; Tothova, Zuzana ; Joseph, Nancy M. ; Lim, Megan S. ; Gilliland, D. Gary ; Morrison, Sean J. / MTOR activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after pten deletion. In: Cell Stem Cell. 2010 ; Vol. 7, No. 5. pp. 593-605.
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AU - Joseph, Nancy M.

AU - Lim, Megan S.

AU - Gilliland, D. Gary

AU - Morrison, Sean J.

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