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PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention

Abstract

Haematopoietic stem cells (HSCs) must achieve a balance between quiescence and activation that fulfils immediate demands for haematopoiesis without compromising long-term stem cell maintenance, yet little is known about the molecular events governing this balance1,2,3. Phosphatase and tensin homologue (PTEN) functions as a negative regulator of the phosphatidylinositol-3-OH kinase (PI(3)K)–Akt pathway, which has crucial roles in cell proliferation, survival, differentiation and migration4,5. Here we show that inactivation of PTEN in bone marrow HSCs causes their short-term expansion, but long-term decline, primarily owing to an enhanced level of HSC activation. PTEN-deficient HSCs engraft normally in recipient mice, but have an impaired ability to sustain haematopoietic reconstitution, reflecting the dysregulation of their cell cycle and decreased retention in the bone marrow niche. Mice with PTEN-mutant bone marrow also have an increased representation of myeloid and T-lymphoid lineages and develop myeloproliferative disorder (MPD)6. Notably, the cell populations that expand in PTEN mutants match those that become dominant in the acute myeloid/lymphoid leukaemia that develops in the later stages of MPD. Thus, PTEN has essential roles in restricting the activation of HSCs, in lineage fate determination, and in the prevention of leukaemogenesis.

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Figure 1: PTEN governs the number and activation state of HSCs and PTEN expression is associated with cyclin D1.
Figure 2: Deletion of PTEN results in HSC expansion and mobilization and impaired bone marrow lodging.
Figure 3: Lineage analysis and competitive repopulation assay.
Figure 4: Loss of PTEN results in myeloproliferative disorder (MPD) and leukaemia.

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References

  1. Li, L. & Xie, T. Stem cell niche: structure and function. Annu. Rev. Cell Dev. Biol. 21, 605–631 (2005)

    Article  CAS  PubMed  Google Scholar 

  2. Heissig, B. et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 109, 625–637 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Arai, F. et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, 149–161 (2004)

    Article  CAS  PubMed  Google Scholar 

  4. Stiles, B., Groszer, M., Wang, S., Jiao, J. & Wu, H. PTENless means more. Dev. Biol. 273, 175–184 (2004)

    Article  CAS  PubMed  Google Scholar 

  5. Cully, M., You, H., Levine, A. J. & Mak, T. W. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nature Rev. Cancer 6, 184–192 (2006)

    Article  CAS  Google Scholar 

  6. Kogan, S. C. et al. Bethesda proposals for classification of nonlymphoid hematopoietic neoplasms in mice. Blood 100, 238–245 (2002)

    Article  CAS  PubMed  Google Scholar 

  7. Zhang, J. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, 836–841 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Kuhn, R., Schwenk, F., Aguet, M. & Rajewsky, K. Inducible gene targeting in mice. Science 269, 1427–1429 (1995)

    Article  ADS  CAS  PubMed  Google Scholar 

  9. Lesche, R. et al. Cre/loxP-mediated inactivation of the murine Pten tumor suppressor gene. Genesis 32, 148–149 (2002)

    Article  CAS  PubMed  Google Scholar 

  10. Christensen, J. L. & Weissman, I. L. Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc. Natl Acad. Sci. USA 98, 14541–14546 (2001)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  11. Vazquez, F. et al. Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex. J. Biol. Chem. 276, 48627–48630 (2001)

    Article  CAS  PubMed  Google Scholar 

  12. He, X. C. et al. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt–β-catenin signaling. Nature Genet. 36, 1117–1121 (2004)

    Article  CAS  PubMed  Google Scholar 

  13. Calvi, L. M. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  14. Kiel, M. J., Yilmaz, O. H., Iwashita, T., Terhorst, C. & Morrison, S. J. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005)

    Article  CAS  PubMed  Google Scholar 

  15. Lapidot, T., Dar, A. & Kollet, O. How do stem cells find their way home? Blood 106, 1901–1910 (2005)

    Article  CAS  PubMed  Google Scholar 

  16. Adams, G. B. et al. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature 439, 599–603 (2006)

    Article  ADS  CAS  PubMed  Google Scholar 

  17. van der Loo, J. C. et al. VLA-5 is expressed by mouse and human long-term repopulating hematopoietic cells and mediates adhesion to extracellular matrix protein fibronectin. J. Clin. Invest. 102, 1051–1061 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Passegue, E., Wagers, A. J., Giuriato, S., Anderson, W. C. & Weissman, I. L. Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J. Exp. Med. 202, 1599–1611 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kondo, M., Weissman, I. L. & Akashi, K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91, 661–672 (1997)

    Article  CAS  PubMed  Google Scholar 

  20. Akashi, K., Traver, D., Miyamoto, T. & Weissman, I. L. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404, 193–197 (2000)

    Article  ADS  CAS  PubMed  Google Scholar 

  21. Groszer, M. et al. PTEN negatively regulates neural stem cell self-renewal by modulating G0–G1 cell cycle entry. Proc. Natl Acad. Sci. USA 103, 111–116 (2006)

    Article  ADS  CAS  PubMed  Google Scholar 

  22. Gregory, M. A., Qi, Y. & Hann, S. R. Phosphorylation by glycogen synthase kinase-3 controls c-myc proteolysis and subnuclear localization. J. Biol. Chem. 278, 51606–51612 (2003)

    Article  CAS  PubMed  Google Scholar 

  23. Cheng, T. et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 287, 1804–1808 (2000)

    Article  ADS  CAS  PubMed  Google Scholar 

  24. Wendel, H. G. et al. Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428, 332–337 (2004)

    Article  ADS  CAS  PubMed  Google Scholar 

  25. Wilson, A. et al. c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev. 18, 2747–2763 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Adolfsson, J. et al. Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic potential. A revised road map for adult blood lineage commitment. Cell 121, 295–306 (2005)

    Article  CAS  PubMed  Google Scholar 

  27. Igarashi, H., Gregory, S. C., Yokota, T., Sakaguchi, N. & Kincade, P. W. Transcription from the RAG1 locus marks the earliest lymphocyte progenitors in bone marrow. Immunity 17, 117–130 (2002)

    Article  CAS  PubMed  Google Scholar 

  28. Akashi, K., Traver, D. & Zon, L. I. The complex cartography of stem cell commitment. Cell 121, 160–162 (2005)

    Article  CAS  PubMed  Google Scholar 

  29. Suzuki, A. et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity 14, 523–534 (2001)

    Article  CAS  PubMed  Google Scholar 

  30. Suzuki, A. et al. Critical roles of Pten in B cell homeostasis and immunoglobulin class switch recombination. J. Exp. Med. 197, 657–667 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank C. Sherr, Y. He and P. Kincade for scientific discussion, and D. di Natale for manuscript proofreading. We are grateful to L. Shannon for assistance in genotyping; J. Wunderlich for flow cytometry assistance; T. Johnson and her co-workers for histology assistance; and H. Marshall for technical assistance. This work was mainly supported by the Stowers Institute for Medical Research. Author Contributions J.Z., X.C.H., J.S.H., L.M.W. and L.L. designed the research; J.Z., X.C.H., T.Y., J.S.H. and S.J. performed the research; J.T.R., D.R., J.S.H., S.J. and K.S.P.-W. provided technical support; H.W. contributed critical reagents; J.Z., X.C.H., J.C.G., J.S.H., S.J., L.M.W. and L.L. analysed data; and L.L., L.M.W. and J.C.G. wrote the paper.

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Correspondence to Linheng Li.

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Supplementary information

Supplementary Figure 1

Targeting efficiency and effect of PTEN deletion on proliferation and the association of pan-PTEN with Cyclin D1 in the LT-HSC population. (PDF 1120 kb)

Supplementary Figure 2

Comparison of HSCs and progenitors in BM, PB, and spleen (Sp), and spleen cellularity in control and PTEN mutant mice. (PDF 1417 kb)

Supplementary Figure 3

Analysis of expression of adhesion molecules and comparison of the migration rate of haematopoietic cells. (PDF 68 kb)

Supplementary Figure 4.

Analysis of the reconstitution ability of spleen-derived donor cells. (PDF 185 kb)

Supplementary Figure 5

Analyses of Acute Lymphoid Leukemia animals using flow cytometry and a new road map of hematopoiesis. (PDF 4413 kb)

Supplementary Methods

This file contains additional details on the methods used in this study. (PDF 112 kb)

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Zhang, J., Grindley, J., Yin, T. et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 441, 518–522 (2006). https://doi.org/10.1038/nature04747

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