Fernandez Maestre, Ines, Wereski, Matthew, Van Haver, Stephane, Leda, Ana, Longhini, Figueiredo, Mistry, Jayna, Trowbridge, Jennifer, Levine, Ross, Amor, Corina (November 2025) Understanding senescence in clonal hematopoiesis. In: UNSPECIFIED.
Abstract
Clonal hematopoiesis (CH) is defined by somatic mutations in hematopoietic cells without overt disease. Common in individuals over 60, CH is linked to an increased risk of acute myeloid leukemia, higher mortality, and poorer cancer survival. It is also associated with age-related conditions such as cardiovascular, pulmonary, and liver diseases. However, the mechanisms driving CH and its connection to aging are poorly understood. Our research aims to explore the impact of aging on the Tet2 knockout (Tet2KO) hematopoietic phenotype and investigate the role of senescence in CH. Through CRISPR/Cas9 screening, we found that Tet2KO hematopoietic stem and progenitor cells (HSPCs) are more reliant on proinflammatory signaling and are more susceptible to inflammatory gene knockout than wild-type (WT) cells; many of which are part of the Senescence-Associated Secretory Phenotype. Further analysis of aged Tet2KO mice confirmed increased levels of inflammatory cytokines, and liver senescence, compared to age-matched WT mice. Bone marrow transplantation experiments showed that donor age did not enhance the clonal fitness of Tet2KO HSPCs, but transplanting Tet2KO cells into aged mice increased mutant cell expansion, suggesting that environmental aging factors influence Tet2KO cell fitness. Lastly, infusion of uPAR-targeting senolytic CAR-T cells significantly reduced myeloid Tet2KO chimerism, indicating that senescence could be targeted to limit the expansion of Tet2KO cells.
| Item Type: | Conference or Workshop Item (Paper) |
|---|---|
| Subjects: | organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence |
| CSHL Authors: | |
| Communities: | CSHL labs > Amor lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 20 November 2025 |
| Date Deposited: | 10 Dec 2025 13:37 |
| Last Modified: | 10 Dec 2025 13:37 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/42033 |
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