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Understanding the role of extrinsic regulators in normal and malignant haematopoiesis



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Belmonte, Miriam 


Numerous studies have highlighted the central role that extrinsic regulators play in both normal and malignant haematopoiesis. Recent evidence suggests that variations in key molecules can directly modulate haematopoietic stem cell (HSC) fate, implicating noncell intrinsic mechanisms for both maintaining homeostasis and for driving disease development. This thesis spans both normal and malignant haematopoiesis, assessing the impact of extrinsic regulators on HSC fate and explores their role in driving the evolution of clonal haematological malignancies. First, I explored the impact of extrinsic regulators on highly purified single HSCs and found that minimising cytokine signalling could sustain a hibernation state in HSCs with the retention of functional properties both in vitro and in vivo. This work established the principle that core functions of HSCs could be maintained in the absence of the bone marrow microenvironment and allowed the identification of key factors dispensable for HSC function (Chapter 3). Next, to understand the role of extrinsic regulators in disease evolution I shifted focus to characterising the cytokine microenvironment in patients with preleukaemic HSCderived disorders known as the myeloproliferative neoplasms (MPNs). This work identified key regulators of the preleukaemic state, including two potential biomarkers of disease evolution, and additional molecules that associated with advanced disease (Chapter 4). This correlation of cytokine levels with specific disease subtypes and disease severity led to the further exploration of one of these molecules in the context of MPNs. The final chapter of my thesis therefore focused on the functional characterisation of IP-10, whose levels correlated with a more severe disease subtype and associated with JAK2 and TET2 mutational status in both patients and mouse models (Chapter 5). Together, these findings highlight the importance of the extrinsic regulators and the haematopoietic microenvironment in influencing cellular outcomes in both the normal and malignant setting and underscores the experimental and clinical potential of modulating extrinsic regulators of HSCs.





Green, Anthony


haematology, haematopoietic stem cells, myeloproliferative neoplasms, extrinsic regulators, inflammatory microenvironment


Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge