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 balance. 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 migration. 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). 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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Signaling through the PTEN-AKT-mTOR pathway upstream of FoxO senses and controls ROS and regulates HSC self-renewal and survival.
“A decline in long-term regeneration capacity of HSCs in mice with conditional deletion of phosphatase and tensin homolog (PTEN) and double deficiency of protein kinase B (AKT) 1 and 2 also indicates that signaling through the PTEN–AKT–mammalian target of rapamycin (mTOR) pathway, upstream of FoxO, senses and controls ROS and regulates HSC self-renewal and survival19–21.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [19]
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- Authors
- Zhang, J., Grindley, J. C., Yin, T., Jayasinghe, S., He, X. C., Ross, J. T., Haug, J. S., Rupp, D., Porter-Westpfahl, K. S., Wiedemann, L. M., Wu, H., & Li, L.
- Affiliations
- Stowers Institute for Medical Research (US)
- University of California, Los Angeles (US)
- Corresponding author
- Li, Linheng
- ORCID
- Venue
- Nature
- Published
- 2006-04-23
- Volume
- 441
- Issue
- 7092
- Pages
- 518-522
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2057403210
- Cited by
- 817
- References
- 30
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 9 · 2023: 19 · 2022: 18 · 2021: 30 · 2020: 22 · 2019: 29 · 2018: 24 · 2017: 29 · 2016: 48 · 2015: 40 · 2014: 58 · 2013: 61 · 2012: 55
- FWCI
- 43.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- PTEN, hematopoietic stem cells, leukemia stem cells, PI3K/Akt signaling, stem cell self-renewal, HSC quiescence, lineage choice, myeloproliferative neoplasms, acute myeloid leukemia, acute lymphoblastic leukemia, rapamycin, bone marrow microenvironment, haematopoietic reconstitution
- MeSH terms
- Animals, Cell Count, Cell Cycle, Hematopoietic Stem Cells, Leukemia, Mutation, Gene Expression, Cell Lineage, Cyclin D1, Cell Proliferation, PTEN Phosphohydrolase, Mice
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