Impaired haematopoietic stem cell differentiation and enhanced skewing towards myeloid progenitors in aged caspase-2-deficient mice
Open accessAbstract
The apoptotic cysteine protease caspase-2 has been shown to suppress tumourigenesis in mice and its reduced expression correlates with poor prognosis in some human malignancies. Caspase-2-deficient mice develop normally but show ageing-related traits and, when challenged by oncogenic stimuli or certain stress, show enhanced tumour development, often accompanied by extensive aneuploidy. As stem cells are susceptible to acquiring age-related functional defects because of their self-renewal and proliferative capacity, we examined whether loss of caspase-2 promotes such defects with age. Using young and aged Casp2−/− mice, we demonstrate that deficiency of caspase-2 results in enhanced aneuploidy and DNA damage in bone marrow (BM) cells with ageing. Furthermore, we demonstrate for the first time that caspase-2 loss results in significant increase in immunophenotypically defined short-term haematopoietic stem cells (HSCs) and multipotent progenitors fractions in BM with a skewed differentiation towards myeloid progenitors with ageing. Caspase-2 deficiency leads to enhanced granulocyte macrophage and erythroid progenitors in aged mice. Colony-forming assays and long-term culture-initiating assay further recapitulated these results. Our results provide the first evidence of caspase-2 in regulating HSC and progenitor differentiation, as well as aneuploidy, in vivo.
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Casp2−/− mice accumulate aneuploid bone marrow cells with aging; Casp2−/− malignant cells have increased aneuploidy vs wild-type.
“In line with a key role for CASP2 in the control of mitotic proficiency, the bone marrow of Casp2−/− mice accumulates aneuploid cells with aging [985], and Casp2−/− malignant cells exhibit increased levels of aneuploidy as compared to their wild-type counterparts [982, 986, 987].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [985]
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- Authors
- Dawar, S., Shahrin, N. H., Sladojevic, N., D'Andrea, R. J., Dorstyn, L., Hiwase, D. K., & Kumar, S.
- Affiliations
- University of South Australia (AU)
- South Australia Pathology (AU)
- Corresponding author
- Kumar, Sharad
- Venue
- Cell Death & Disease
- Published
- 2016-12-01
- Volume
- 7
- Issue
- 12
- Pages
- e2509-e2509
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC5260989
- OpenAlex
- W2559212833
- Cited by
- 30
- References
- 39
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 6 · 2018: 4 · 2017: 4
- FWCI
- 4.44
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UniSA Research Outputs Repository (University of South Australia) (submittedVersion, cc-by)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by)
- Funders
- Medical Research Council
- National Health and Medical Research Council (1103006, 1043057)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- caspase-2, hematopoietic stem cells, aging, aneuploidy, DNA damage, bone marrow, progenitor cell differentiation, tumourigenesis, long-term culture-initiating cells
- MeSH terms
- Aging, Aneuploidy, Animals, Cell Differentiation, Cells, Cultured, DNA Damage, Hematopoietic Stem Cells, Mice, Inbred C57BL, Mice, Knockout, Myeloid Progenitor Cells, Caspase 2
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