Genetic identification and functional dissection of the cellular interactome of haematopoietic stem cells and leukaemic stem cells

Blood stem cells (BSCs) produce all red and white blood cells that the body needs to survive and fight infection. BSCs sit in specialized pockets, so-called "niches" of cells in the bone marrow (BM). These niches are critical to regulate BSC health, and therefore help to generate all blood cells. The precise identity of the cells that form these niches is unknown. As we age, the environment that surrounds BSCs changes, and this can lead to health issues including anaemia or a weaker immune system. Moreover, if BSCs are damaged they can transform into leukaemic stem cells (LSCs). LSCs are able to further modify BM niches for their own benefit to promote cancer progression. Thus, it is very important to know exactly how the BM environment changes with age or disease so we can prevent and treat associated conditions, such as leukaemia. BSCs are used in BM transplantation to treat different blood diseases including leukaemia, anaemia, or sickle cell disease. Patients also need them to recover from anti-cancer treatments such as chemotherapy. Every year worldwide, thousands of people require a BM transplant. For the transplant to be successful, the donor has to be compatible with the recipient. Due to donor shortages, this can leave some patients without the transplant they need. To eliminate the continuous need of BM donors, scientists aim to expand BSCs in the laboratory, as this will lead to never-ending supply of suitable donor cells. Unfortunately, this is currently not possible as BSCs cannot be efficiently expanded in the laboratory. BSCs naturally divide in our bodies during infancy, but once we reach adulthood, they rarely divide. As such, our research begins with studying how BSCs expand during infancy. If we learn about how BSCs divide naturally within the body, we will be able to imitate this in the laboratory to get continuous supplies for BM transplants. Additionally, the precise composition of the niches that support leukaemic stem cells is also unknown. LSCs produce large numbers of immature cells, known as blasts, which rapidly divide, and interfere normal blood cell function. Chemotherapy is able to kill these blasts, but sometimes does not eradicate all the LSCs. Following therapy, the remaining LSCs are thought to fuel disease relapses. Since LSCs rely on their niches which nurture them, an alternative therapeutic approach is to cut off the lifeline of LSCs by targeting their niche cells. Hence, I aim to: 1) identify the niches that support healthy BSCs; and 2) reveal the niche components that are altered during ageing and that support LSCs during leukaemia. By understanding the differences between health and disease states we can develop therapies to prevent cancer emergence, and treat and cure patients. Notably, this area of research has been explored world-wide due to its high clinical interest. Although scientific advances have been made, current technologies lack the required precision to identify and isolate the niche cells. My research focuses around a technology that allows to fluorescently mark niche cells that are in physical contact with the BSCs or LSCs. Once the niche cells are labelled, we can isolate these cells from the bone marrow, with significantly more precision than the most skillful surgeon. We can then study these niche cells at the molecular level, and reveal how these niche cells change during development, adulthood, ageing and disease, including leukaemia. In sum, this research is of critical scientific and clinical importance and will result in: 1) eradication of LSCs, avoiding leukaemia relapses, 2) treating the effects of ageing on blood, 3) the expansion of BSCs in laboratory culture dishes for transplantation, which will decrease the need for bone marrow donors and will allow for the investigation of other blood diseases.