The influence of INK4 proteins on growth and self-renewal kinetics of hematopoietic progenitor cells.
Abstract
This study investigated the influence of expression of proteins of the INK4 family, particularly p16, on the growth and self-renewal kinetics of hematopoietic cells. First, retrovirus-mediated gene transfer (RMGT) was used to restore p16(INK4a) expression in the p16(INK4a)-deficient lymphoid and myeloid cell lines BV173 and K562, and it was confirmed that this inhibited their growth. Second, to sequester p16(INK4a) and related INK4 proteins, cyclin-dependent kinase 4 (CDK4) was retrovirally transduced into normal human CD34(+) bone marrow cells and then cultured in myeloid colony-forming cell (CFC) assays. The growth of CDK4-transduced colonies was more rapid; the cell-doubling time was reduced; and, upon replating, the colonies produced greater yields of secondary colonies than mock-untransduced controls. Third, colony formation was compared by marrow cells from p16(INK4a-/-) mice and wild-type mice. The results from p16(INK4a-/-) marrow were similar to those from CDK4-transduced human CFCs, in terms of growth rate and replating ability, and were partially reversed by RMGT of p16(INK4a). Lines of immature granulocytic cells were raised from 15 individual colonies grown from the marrow of p16(INK4a-/-) mice. These had a high colony-forming ability (15%) and replating efficiency (96.7%). The p16(INK4a-/-) cell lines readily became growth factor-independent upon cytokine deprivation. Taken together, these results demonstrate that loss of INK4 proteins, in particular p16(INK4a), increases the growth rate of myeloid colonies in vitro and, more importantly, confers an increased ability for clonal expansion on hematopoietic progenitor cells.
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Knockout of p16 increases the life-span of HSCs by promoting HSC self-renewal.
“but knockout of p16 increases the life-span of HSCs by promoting HSC self-renewal.16-19”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [17]
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- Authors
- Lewis, J. L., Chinswangwatanakul, W., Zheng, B., Marley, S. B., Nguyen, D. X., Cross, N. C. P., Banerji, L., Glassford, J., Thomas, N. S. B., Goldman, J. M., Lam, E. W.-F., & Gordon, M. Y.
- Affiliations
- King's College London (GB)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2001-05-01
- Volume
- 97
- Issue
- 9
- Pages
- 2604-2610
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2120435486
- Cited by
- 53
- References
- 49
- Citations by year
- 2022: 1 · 2021: 1 · 2020: 1 · 2018: 1 · 2015: 2 · 2014: 3 · 2013: 3 · 2012: 3
- FWCI
- 2.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- p16INK4a, hematopoietic progenitor cells, self-renewal, cell growth kinetics, CDK4, cyclin-dependent kinases, clonal expansion, clonogenicity, growth factor independence, myeloid colony formation, CD34+ bone marrow cells
- MeSH terms
- Animals, Cell Division, Cell Line, Gene Expression Regulation, Hematopoietic Stem Cells, Humans, Genes, Tumor Suppressor, Cyclin-Dependent Kinase Inhibitor p16, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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