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Title: In vivo imaging of the dynamic interactions of acute leukaemias with the bone marrow microenvironment
Author: Ferreira Duarte, Delfim Diogo
ISNI:       0000 0004 8504 5864
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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Adult haematopoietic stem cells (HSC) reside in the bone marrow (BM) microenvironment, or niche, where they are regulated by several cell types including osteoblasts, endothelial cells and Nestin-expressing perivascular cells, and by niche-derived signals, such as CXCL12. In parallel, leukaemia growth and chemoresistance have been proposed to be dependent on an analogous malignant microenvironment. Using a murine model of MLL-AF9 driven acute myeloid leukaemia (AML), I show that AML outcompetes non-malignant haematopoiesis by gradual elimination of stroma cells, endosteal endothelium and osteoblastic cells. I further demonstrate that blood vessels in AML-burdened mice are more cell-permeable and likely contribute to loss of haematopoietic cells. The rescue of the endosteal vascular microenvironment in AML rescues HSC loss and improves chemotherapy efficacy (Chapter 3). To address the reverse question, i.e. whether the microenvironment influences disease progression, I studied a mouse model of T-cell acute lymphoblastic leukaemia (T-ALL) driven by constitutively active Notch1. Our group had previously shown that T-ALL progression is independent from particular niches. Here, I show that chemoresistant T-ALL cells are also niche-independent and highly motile, maintaining very transient interactions with surrounding microenvironments (Chapter 4). Studying the in vivo behaviour of Notch-1 T-ALL and MLL-AF9 cells in parallel, I observed that chemoresistant AML cells, in contrast with T-ALL, are less migratory than naïve ones. I also show that AMD3100, an antagonist of CXCR4 (the receptor of CXCL12), inhibits the migration of treatment-naïve and chemoresistant T-ALL cell migration. In contrast, AML cell behaviour remains unaltered after CXCR4 inhibition, likely because of disease-specific, more complex interactions with the BM microenvironment (Chapter 5). These results support the importance of cell-intrinsic and overall tissue influence rather than stroma-specific signals supporting chemoresistant T-ALL. Additionally I show that therapies targeting the endosteal vasculature could potentially improve existing AML therapeutic regimes. The different nature of leukaemia-microenvirnment interactions for the two diseases is further demonstrated by the observation that CXCR4 inhibition affects T-ALL but not AML cell migration within the BM space.
Supervisor: Lo Celso, Cristina Sponsor: Fundacao para a Ciencia e a Tecnologia
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral