Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells

Ömer H. Yilmaz, Riccardo Valdez, Brian K. Theisen, Wei Guo, David O. Ferguson, Hong Wu, Sean J. Morrison

Research output: Contribution to journalArticle

1028 Citations (Scopus)

Abstract

Recent advances have highlighted extensive phenotypic and functional similarities between normal stem cells and cancer stem cells. This raises the question of whether disease therapies can be developed that eliminate cancer stem cells without eliminating normal stem cells. Here we address this issue by conditionally deleting the Pten tumour suppressor gene in adult haematopoietic cells. This led to myeloproliferative disease within days and transplantable leukaemias within weeks. Pten deletion also promoted haematopoietic stem cell (HSC) proliferation. However, this led to HSC depletion via a cell-autonomous mechanism, preventing these cells from stably reconstituting irradiated mice. In contrast to leukaemia-initiating cells, HSCs were therefore unable to maintain themselves without Pten. These effects were mostly mediated by mTOR as they were inhibited by rapamycin. Rapamycin not only depleted leukaemia-initiating cells but also restored normal HSC function. Mechanistic differences between normal stem cells and cancer stem cells can thus be targeted to deplete cancer stem cells without damaging normal stem cells.

Original languageEnglish (US)
Pages (from-to)475-482
Number of pages8
JournalNature
Volume441
Issue number7092
DOIs
StatePublished - May 25 2006

Fingerprint

Hematopoietic Stem Cells
Neoplastic Stem Cells
Leukemia
Stem Cells
Sirolimus
Tumor Suppressor Genes
Cell Proliferation
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Yilmaz, Ö. H., Valdez, R., Theisen, B. K., Guo, W., Ferguson, D. O., Wu, H., & Morrison, S. J. (2006). Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature, 441(7092), 475-482. https://doi.org/10.1038/nature04703

Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. / Yilmaz, Ömer H.; Valdez, Riccardo; Theisen, Brian K.; Guo, Wei; Ferguson, David O.; Wu, Hong; Morrison, Sean J.

In: Nature, Vol. 441, No. 7092, 25.05.2006, p. 475-482.

Research output: Contribution to journalArticle

Yilmaz, ÖH, Valdez, R, Theisen, BK, Guo, W, Ferguson, DO, Wu, H & Morrison, SJ 2006, 'Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells', Nature, vol. 441, no. 7092, pp. 475-482. https://doi.org/10.1038/nature04703
Yilmaz ÖH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature. 2006 May 25;441(7092):475-482. https://doi.org/10.1038/nature04703
Yilmaz, Ömer H. ; Valdez, Riccardo ; Theisen, Brian K. ; Guo, Wei ; Ferguson, David O. ; Wu, Hong ; Morrison, Sean J. / Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. In: Nature. 2006 ; Vol. 441, No. 7092. pp. 475-482.
@article{76cf1d4160d84f1ba11d9343308c9f30,
title = "Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells",
abstract = "Recent advances have highlighted extensive phenotypic and functional similarities between normal stem cells and cancer stem cells. This raises the question of whether disease therapies can be developed that eliminate cancer stem cells without eliminating normal stem cells. Here we address this issue by conditionally deleting the Pten tumour suppressor gene in adult haematopoietic cells. This led to myeloproliferative disease within days and transplantable leukaemias within weeks. Pten deletion also promoted haematopoietic stem cell (HSC) proliferation. However, this led to HSC depletion via a cell-autonomous mechanism, preventing these cells from stably reconstituting irradiated mice. In contrast to leukaemia-initiating cells, HSCs were therefore unable to maintain themselves without Pten. These effects were mostly mediated by mTOR as they were inhibited by rapamycin. Rapamycin not only depleted leukaemia-initiating cells but also restored normal HSC function. Mechanistic differences between normal stem cells and cancer stem cells can thus be targeted to deplete cancer stem cells without damaging normal stem cells.",
author = "Yilmaz, {{\"O}mer H.} and Riccardo Valdez and Theisen, {Brian K.} and Wei Guo and Ferguson, {David O.} and Hong Wu and Morrison, {Sean J.}",
year = "2006",
month = "5",
day = "25",
doi = "10.1038/nature04703",
language = "English (US)",
volume = "441",
pages = "475--482",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7092",

}

TY - JOUR

T1 - Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells

AU - Yilmaz, Ömer H.

AU - Valdez, Riccardo

AU - Theisen, Brian K.

AU - Guo, Wei

AU - Ferguson, David O.

AU - Wu, Hong

AU - Morrison, Sean J.

PY - 2006/5/25

Y1 - 2006/5/25

N2 - Recent advances have highlighted extensive phenotypic and functional similarities between normal stem cells and cancer stem cells. This raises the question of whether disease therapies can be developed that eliminate cancer stem cells without eliminating normal stem cells. Here we address this issue by conditionally deleting the Pten tumour suppressor gene in adult haematopoietic cells. This led to myeloproliferative disease within days and transplantable leukaemias within weeks. Pten deletion also promoted haematopoietic stem cell (HSC) proliferation. However, this led to HSC depletion via a cell-autonomous mechanism, preventing these cells from stably reconstituting irradiated mice. In contrast to leukaemia-initiating cells, HSCs were therefore unable to maintain themselves without Pten. These effects were mostly mediated by mTOR as they were inhibited by rapamycin. Rapamycin not only depleted leukaemia-initiating cells but also restored normal HSC function. Mechanistic differences between normal stem cells and cancer stem cells can thus be targeted to deplete cancer stem cells without damaging normal stem cells.

AB - Recent advances have highlighted extensive phenotypic and functional similarities between normal stem cells and cancer stem cells. This raises the question of whether disease therapies can be developed that eliminate cancer stem cells without eliminating normal stem cells. Here we address this issue by conditionally deleting the Pten tumour suppressor gene in adult haematopoietic cells. This led to myeloproliferative disease within days and transplantable leukaemias within weeks. Pten deletion also promoted haematopoietic stem cell (HSC) proliferation. However, this led to HSC depletion via a cell-autonomous mechanism, preventing these cells from stably reconstituting irradiated mice. In contrast to leukaemia-initiating cells, HSCs were therefore unable to maintain themselves without Pten. These effects were mostly mediated by mTOR as they were inhibited by rapamycin. Rapamycin not only depleted leukaemia-initiating cells but also restored normal HSC function. Mechanistic differences between normal stem cells and cancer stem cells can thus be targeted to deplete cancer stem cells without damaging normal stem cells.

UR - http://www.scopus.com/inward/record.url?scp=33646376411&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33646376411&partnerID=8YFLogxK

U2 - 10.1038/nature04703

DO - 10.1038/nature04703

M3 - Article

C2 - 16598206

AN - SCOPUS:33646376411

VL - 441

SP - 475

EP - 482

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7092

ER -