Mechanistic study of how specific mutations associated with clonal haematopoiesis impact human haematopoietic stem cell function

Summary

Blood cell production is maintained by rare haematopoietic stem cells (HSC). In younger individuals, there are approximately 100,000 HSCs contributing to blood formation. However, with age, HSCs acquire mutations, some of which provide them with a positive clonal selection advantage.

Individuals with clonal haematopoiesis, who carry specific mutations over a certain threshold, have increased risk of blood cancers and cardiovascular disease. Our laboratory recently demonstrated that clonal haematopoiesis is pervasive and that in individuals over the age of 70, less than 20 mutated HSC clones give rise to 1-30% of all blood cells (Mitchell et al., Nature, 2022).

In addition, our team and others have identified a large number of mutations that impart a clonal advantage to HSCs. However the cellular and molecular mechanisms by which they do so remain unknown.

Project aims

This PhD project will focus on quantifying the impact of specific mutations (variants) driving clonal expansion on HSC function. 

For this, the student will introduce variants via CRISPR gene editing in primary human HSCs then will use tractable state-of-the-art methods to comprehensively assess HSC function, including novel in vitro HSC expansion methods (Sakurai et al., Nature, 2023).

This work will be complemented with the study of native mutations in humans.  Collectively the project will provide new mechanistic insights into how clonal haematopoiesis related mutations alter blood formation and how that leads to increased disease risk.

Contact details

Professor Elisa Laurenti - el422@cam.ac.uk

Opportunities

This project is open to applicants who want to do a:

• PhD