Just before Christmas on December 21st, our PhD student Flavia Peci defended her thesis "Genomic Safety of Transplantation; characterising the Mutational Consequences of Treatment in Hematopoietic Stem Cells".
Since the first allogeneic hematopoietic stem cell transplantation (HSCT) in 1957, treatments have improved, but HSCT patients still face life-threatening complications. From 1957 to 2019, approximately 1.5 million patients worldwide underwent a stem cell transplant. Therefore, minimizing the toxicity of the treatment and thereby improving survival without disease recurrence remains crucial. Some of the open questions about HSCT include: what is the contribution of successfully transplanted stem cells to the regeneration of the hematopoietic system, and what is the influence of transplantation on the genetic stability of the transplanted cells?
The aging process affects the functioning of the hematopoietic system and increases the risk of cancer due to factors such as the accumulation of somatic mutations and telomere erosion in stem cells. At the age of 60, hematopoietic stem and progenitor cells (HSPCs) have around 1,000 somatic mutations in their genome. Through sequencing techniques such as Next Generation Sequencing (NGS), these mutations can be detected, and their impact can be determined. Single-cell sequencing enables tracking mutations and clonal relationships in the hematopoietic system, which is important for understanding health and disease. For genetically damaged HSPCs, such as those in Fanconi Anemia, new techniques like primary template amplification (PTA) are needed to obtain sufficient DNA from a single cell for genome analysis.HSCT conditioning before transplantation often involves chemotherapy and radiation, which can damage the bone marrow niche. This can affect the function of stem cells and, thus, hematopoietic regeneration. This damage increases the risk of morbidity and mortality in HSCT patients.
After transplantation, patients are susceptible to infections, necessitating the use of antiviral nucleoside analog (NA) drugs. Although their toxicity has been tested in vitro, their mutagenic and carcinogenic effects on patient's stem cells remain unknown. Understanding the long-term effects of antiviral NA drugs is essential for improving HSCT outcomes.
The thesis can be found at the website of the UU library