Competition between healthy and malignant haematopoiesis: from cellular mechanisms to interventions that maintain stem cells in their bone marrow niche
File(s)
Author(s)
Pirillo, Chiara
Type
Thesis
Abstract
Haematopoietic stem cells (HSC) reside in the bone marrow (BM) microenvironment where, despite being very rare (<0.015% of BM haematopoietic
cells), they maintain the turnover of all blood cells through a balance of quiescence, self-renewal and differentiation. Disruption of HSC function and of the BM microenvironment are key characteristics of Acute Myeloid Leukaemia (AML) progression. AML develops in both children and adults and major
symptoms arise due to the loss of healthy haematopoietic cells. Although several hypotheses
have been proposed to explain what factors contribute to this, the mechanisms behind HSC
loss remain unknown. Here, using a murine model of MLL-AF9 driven AML, I show that AML competes against healthy haematopoietic cells for space, causing enhanced egress of haematopoietic cells from the BM into the circulation (Chapter 3). Using intravital microscopy (IVM), I show that during AML development healthy cells leave the BM in clusters and I hypothesise a role for extracellular matrix regulation and vascular leakiness in causing that.
Interestingly, I demonstrate a clear association between the extent of BM infiltration and the
number of HSCs found in the spleen and liver. Transplantation assays show that extramedullary
HSCs are functional and able to reconstitute the BM of lethally irradiated mice (Chapter 4).
Thus, extramedullary haematopoiesis (EMH) could represent a way to guarantee overall blood
cell production in the short-term. I subsequently establish a novel therapeutic approach involving a metalloproteinase inhibitor, prinomastat (AG3340), which aims to delay AML progression and maintain healthy cells within their niche. Under prinomastat treatment, vascular leakiness is reduced, AML grows less in the BM microenvironment, with leukemic
blasts showing reduced proliferation and migration speed as well as increased apoptosis. Most
importantly, prinomastat treatment significantly enhanced residual haematopoiesis, reduced
the extent of EMH in both spleen and liver, and improved survival following chemotherapy
treatment (Chapter 5).
cells), they maintain the turnover of all blood cells through a balance of quiescence, self-renewal and differentiation. Disruption of HSC function and of the BM microenvironment are key characteristics of Acute Myeloid Leukaemia (AML) progression. AML develops in both children and adults and major
symptoms arise due to the loss of healthy haematopoietic cells. Although several hypotheses
have been proposed to explain what factors contribute to this, the mechanisms behind HSC
loss remain unknown. Here, using a murine model of MLL-AF9 driven AML, I show that AML competes against healthy haematopoietic cells for space, causing enhanced egress of haematopoietic cells from the BM into the circulation (Chapter 3). Using intravital microscopy (IVM), I show that during AML development healthy cells leave the BM in clusters and I hypothesise a role for extracellular matrix regulation and vascular leakiness in causing that.
Interestingly, I demonstrate a clear association between the extent of BM infiltration and the
number of HSCs found in the spleen and liver. Transplantation assays show that extramedullary
HSCs are functional and able to reconstitute the BM of lethally irradiated mice (Chapter 4).
Thus, extramedullary haematopoiesis (EMH) could represent a way to guarantee overall blood
cell production in the short-term. I subsequently establish a novel therapeutic approach involving a metalloproteinase inhibitor, prinomastat (AG3340), which aims to delay AML progression and maintain healthy cells within their niche. Under prinomastat treatment, vascular leakiness is reduced, AML grows less in the BM microenvironment, with leukemic
blasts showing reduced proliferation and migration speed as well as increased apoptosis. Most
importantly, prinomastat treatment significantly enhanced residual haematopoiesis, reduced
the extent of EMH in both spleen and liver, and improved survival following chemotherapy
treatment (Chapter 5).
Version
Open Access
Date Issued
2020-09
Date Awarded
2021-02
Copyright Statement
Creative Commons Attribution NonCommercial NoDerivatives Licence
Advisor
Lo Celso, Cristina
Sponsor
Bloodwise (Organization)
Publisher Department
Life Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)