Title: In vivo tracking of haematopoietic stem and progenitor cells under normal physiological conditions and during the development of leukaemia
Funder: Cancer Research UK

Abstract: Blood stem cells replenish all blood cell lineages, but lose this ability when leukaemia develops. This study investigates the interactions between developing leukaemia and normal stem cells to learn how the disease overcomes healthy blood production. Ultimately, results will point to new anti-leukaemia treatments that protect the patients' stem cells. Adult haematopoietic stem cells (HSC) maintain the turnover of peripheral blood and immune system cells by tightly balancing quiescence, self-renewal and differentiation. Leukaemia develops from defects in such balance and overtakes normal haematopoiesis. While multiple interactions between HSC and the bone marrow microenvironment are key for correct haematopoiesis, little is known about the interrelationship between leukaemia cells, normal HSC and the bone marrow microenvironment. In some leukaemias functional HSC are retained even though downstream haematopoiesis is disrupted. HSC transplanted in mice burdened with advanced disease were unable to reach their physiological niche and were instead attracted towards an inhibitory environment. In vivo imaging technologies are a novel approach allowing direct observation of haematopoietic cells within the bone marrow and correlating HSC position to function.Currently available leukaemia treatments rely on severe myeloablation. Understanding how leukaemia affects normal HSC function starting from early stages of disease until the occurrence of clinical signs will allow planning, developing and testing a new generation of molecular interventions able to eradicate leukaemia while preserving and triggering normal HSC function.The proposed study has three specific aims:1. Analysis of the spatial relationship between transplanted HSC and progenitors and leukaemia initiating cells (LIC) will test whether HSC and LIC compete for niche space. LIC could directly displace HSC or affect them indirectly by producing inhibitory factors or altering their physiological microenvironment.2. In vivo tracking of endogenous HSC fate choice will indicate whether haematopoiesis is normally maintained through specific HSC division patterns and outcomes. The resulting haematopoietic tissue architecture, sufficiently flexible to respond to external stimuli, would be profoundly affected by leukaemia development.3. Direct assessment of haematopoiesis deregulation during leukaemia development will show whether leukaemia affects haematopoiesis by blocking generation of all differentiated progeny or by subtly altering HSC proliferation dynamics and outcomes.My research group will take advantage of bone marrow in vivo imaging protocols I recently developed to monitor real-time interactions between HSC,,LIC and their microenvironment. MLL-AF9 and BCR-ABL transduction of mouse bone marrow will provide two distinct models of acute and chronic myeloid leukaemia. The two clinically distinct diseases (fast developing during childhood vs. slowly progressing during old age) are likely to develop with different bone marrow kinetics. The generation of a new mouse reporter system allowing direct observation of HSC differentiation will reveal haematopoietic tissue architecture in steady-state conditions, in transplantation settings and in the presence of developing leukaemia.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS