Leveraging technological advances to uncover metabolic drivers of clonal hematopoiesis
(2026)
Files
PhD_Thesis-Celina_Nielsen_Final.pdf
Embargo Access until 2027-07-01 - Adobe PDF
- 19.29 MB
Details
- Authors
- Supervisors
; - Abstract
- (en) Clonal hematopoiesis (CH) is an age-associated condition driven by somatic mutations in hematopoietic stem and progenitor cells (HSPCs), increasing the risk of hematological malignancies, cardiovascular disease, and multiple other inflammation-related disorders. Since the discovery of CH, efforts have focused on understanding how mutant clones contribute to disease and whether their competitive advantage can be therapeutically targeted. In this thesis, we optimized protocols for HSPC isolation and low-input metabolomics, which enabled the identification of increased inositol and valine metabolism in Dnmt3a-R878H HSPCs. Treatment with valproic acid, an inositol synthesis inhibitor, reduced the competitive advantage of mutant HSPCs ex vivo and in vivo, although effects appeared to extend beyond inositol metabolism. Additionally, valine supplementation enhanced mutant HSC fitness, whereas inhibition of valine degradation using BAY-069 reduced their self-renewal. These results reveal metabolic vulnerabilities of DNMT3A-mutant CH and suggest potential therapeutic strategies.
- Affiliations
Citations
Nielsen, C. (2026). Leveraging technological advances to uncover metabolic drivers of clonal hematopoiesis. https://hdl.handle.net/2078.5/277762