Dr Elisa Laurenti, University of Cambridge
Dr Liran Shlush, Weizmann Institute of Science
Ageing has a severe impact on the blood and immune system that results in increased incidence of infections, anaemia and blood cancers in the elderly. This is caused by dysfunction of blood stem and progenitors cells, those cells responsible for the daily production of blood and immune cell types. It has recently become clear that stem cells acquire mutations identical to those found in blood cancers (pre-leukaemic mutations; pLMs) as they age. These pre-leukaemic stem and progenitor cells (preL-HSPCs) are initially capable of producing functional blood but can over time either lead
to a defective immune system or acquire more mutations and generate blood cancers. In particular, preL-HSPCs can differentiate into mature immune cells carrying pLMs. As a consequence, it is possible that the immune dysfunction observed with ageing is related to pLMs. A promising avenue to prevent and treat blood cancers and this immune dysfunction is to develop therapies that target preL-HSPCs to either eliminate them or restore their healthy state. However, the mechanisms by which preL-HSPCs and immune cells acquire their abnormal characteristics remain unclear to date.
In this project, Dr Laurenti and Dr Shlush used state of the art in vitro and in vivo techniques to derive a comprehensive understanding of how the most common pLMs change the function and the molecular networks of blood stem progenitor and mature cells. They will also study if and how these cells outcompete non-mutated cells over long periods of time, and how pLMs influence mature myeloid cells function.
Through this work, the researchers aim to get a better understanding how the blood compartment ages and how some of these age-related changes set the ground for the development of blood cancers. This project will also generate an important resource describing the molecular behaviour of pre-leukaemic mutations - Hematopoietic stem and progenitor cell (preL-HSPCs). This information is currently lacking and is absolutely necessary to devise regenerative medicine interventions to restore preL-HSPCs. These hold great promise to prevent the reappearance of blood cancer, or to more generally palliate the detrimental effects of ageing on blood formation and immune function.