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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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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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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DOI: https://doi.org/10.1038/nature04747
