Temporal changes in PTEN and mTORC2 regulation of hematopoietic stem cell self-renewal and leukemia suppression

Jeffrey A. Magee, Tsuneo Ikenoue, Daisuke Nakada, Jae Y. Lee, Kun Liang Guan, Sean J. Morrison

Research output: Contribution to journalArticle

112 Citations (Scopus)

Abstract

Pten deletion from adult mouse hematopoietic cells activates the PI3-kinase pathway, inducing hematopoietic stem cell (HSC) proliferation, HSC depletion, and leukemogenesis. Pten is also mutated in human leukemias, but rarely in early childhood leukemias. We hypothesized that this reflects developmental changes in PI3-kinase pathway regulation. Here we show that Rictor deletion prevents leukemogenesis and HSC depletion after Pten deletion in adult mice, implicating mTORC2 activation in these processes. However, Rictor deletion had little effect on the function of normal HSCs. Moreover, Pten deletion from neonatal HSCs did not activate the PI3-kinase pathway or promote HSC proliferation, HSC depletion, or leukemogenesis. Pten is therefore required in adult, but not neonatal, HSCs to negatively regulate mTORC2 signaling. This demonstrates that some critical tumor suppressor mechanisms in adult cells are not required by neonatal cells. Developmental changes in key signaling pathways therefore confer temporal changes upon stem cell self-renewal and tumor suppressor mechanisms.

Original languageEnglish (US)
Pages (from-to)415-428
Number of pages14
JournalCell Stem Cell
Volume11
Issue number3
DOIs
StatePublished - Sep 7 2012

Fingerprint

Hematopoietic Stem Cells
Leukemia
Phosphatidylinositol 3-Kinases
Cell Proliferation
Neoplasms
TOR complex 2
Cell Self Renewal

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine
  • Genetics

Cite this

Temporal changes in PTEN and mTORC2 regulation of hematopoietic stem cell self-renewal and leukemia suppression. / Magee, Jeffrey A.; Ikenoue, Tsuneo; Nakada, Daisuke; Lee, Jae Y.; Guan, Kun Liang; Morrison, Sean J.

In: Cell Stem Cell, Vol. 11, No. 3, 07.09.2012, p. 415-428.

Research output: Contribution to journalArticle

Magee, Jeffrey A. ; Ikenoue, Tsuneo ; Nakada, Daisuke ; Lee, Jae Y. ; Guan, Kun Liang ; Morrison, Sean J. / Temporal changes in PTEN and mTORC2 regulation of hematopoietic stem cell self-renewal and leukemia suppression. In: Cell Stem Cell. 2012 ; Vol. 11, No. 3. pp. 415-428.
@article{1134614370524f3881c618e25569e013,
title = "Temporal changes in PTEN and mTORC2 regulation of hematopoietic stem cell self-renewal and leukemia suppression",
abstract = "Pten deletion from adult mouse hematopoietic cells activates the PI3-kinase pathway, inducing hematopoietic stem cell (HSC) proliferation, HSC depletion, and leukemogenesis. Pten is also mutated in human leukemias, but rarely in early childhood leukemias. We hypothesized that this reflects developmental changes in PI3-kinase pathway regulation. Here we show that Rictor deletion prevents leukemogenesis and HSC depletion after Pten deletion in adult mice, implicating mTORC2 activation in these processes. However, Rictor deletion had little effect on the function of normal HSCs. Moreover, Pten deletion from neonatal HSCs did not activate the PI3-kinase pathway or promote HSC proliferation, HSC depletion, or leukemogenesis. Pten is therefore required in adult, but not neonatal, HSCs to negatively regulate mTORC2 signaling. This demonstrates that some critical tumor suppressor mechanisms in adult cells are not required by neonatal cells. Developmental changes in key signaling pathways therefore confer temporal changes upon stem cell self-renewal and tumor suppressor mechanisms.",
author = "Magee, {Jeffrey A.} and Tsuneo Ikenoue and Daisuke Nakada and Lee, {Jae Y.} and Guan, {Kun Liang} and Morrison, {Sean J.}",
year = "2012",
month = "9",
day = "7",
doi = "10.1016/j.stem.2012.05.026",
language = "English (US)",
volume = "11",
pages = "415--428",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - Temporal changes in PTEN and mTORC2 regulation of hematopoietic stem cell self-renewal and leukemia suppression

AU - Magee, Jeffrey A.

AU - Ikenoue, Tsuneo

AU - Nakada, Daisuke

AU - Lee, Jae Y.

AU - Guan, Kun Liang

AU - Morrison, Sean J.

PY - 2012/9/7

Y1 - 2012/9/7

N2 - Pten deletion from adult mouse hematopoietic cells activates the PI3-kinase pathway, inducing hematopoietic stem cell (HSC) proliferation, HSC depletion, and leukemogenesis. Pten is also mutated in human leukemias, but rarely in early childhood leukemias. We hypothesized that this reflects developmental changes in PI3-kinase pathway regulation. Here we show that Rictor deletion prevents leukemogenesis and HSC depletion after Pten deletion in adult mice, implicating mTORC2 activation in these processes. However, Rictor deletion had little effect on the function of normal HSCs. Moreover, Pten deletion from neonatal HSCs did not activate the PI3-kinase pathway or promote HSC proliferation, HSC depletion, or leukemogenesis. Pten is therefore required in adult, but not neonatal, HSCs to negatively regulate mTORC2 signaling. This demonstrates that some critical tumor suppressor mechanisms in adult cells are not required by neonatal cells. Developmental changes in key signaling pathways therefore confer temporal changes upon stem cell self-renewal and tumor suppressor mechanisms.

AB - Pten deletion from adult mouse hematopoietic cells activates the PI3-kinase pathway, inducing hematopoietic stem cell (HSC) proliferation, HSC depletion, and leukemogenesis. Pten is also mutated in human leukemias, but rarely in early childhood leukemias. We hypothesized that this reflects developmental changes in PI3-kinase pathway regulation. Here we show that Rictor deletion prevents leukemogenesis and HSC depletion after Pten deletion in adult mice, implicating mTORC2 activation in these processes. However, Rictor deletion had little effect on the function of normal HSCs. Moreover, Pten deletion from neonatal HSCs did not activate the PI3-kinase pathway or promote HSC proliferation, HSC depletion, or leukemogenesis. Pten is therefore required in adult, but not neonatal, HSCs to negatively regulate mTORC2 signaling. This demonstrates that some critical tumor suppressor mechanisms in adult cells are not required by neonatal cells. Developmental changes in key signaling pathways therefore confer temporal changes upon stem cell self-renewal and tumor suppressor mechanisms.

UR - http://www.scopus.com/inward/record.url?scp=84866064701&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866064701&partnerID=8YFLogxK

U2 - 10.1016/j.stem.2012.05.026

DO - 10.1016/j.stem.2012.05.026

M3 - Article

VL - 11

SP - 415

EP - 428

JO - Cell Stem Cell

JF - Cell Stem Cell

SN - 1934-5909

IS - 3

ER -