Investigation of the role of bone marrow stromal cells in the microenvironment of acute myeloid leukaemia

Abdul-Aziz, Amina (2017) Investigation of the role of bone marrow stromal cells in the microenvironment of acute myeloid leukaemia. Doctoral thesis, University of East Anglia.

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Acute myeloid leukaemia (AML) is an aggressive malignancy of the
haematopoietic system. With a median age of approximately 70 years at
diagnosis, survival rates for AML patients lag behind other haematological
malignancies. This is in part, due to existing comorbidities and patient inability
to tolerate intensive chemotherapy. Moreover, chemotherapy mainly targets
AML cells in the peripheral blood (PB) but not those harboured in the bone
marrow (BM). While studies focusing on the malignant blasts helped achieve
advances in understanding AML biology and chemoresistance, less is
understood about the role of the bone marrow microenvironment (BMM) in the
progression of AML. It is predicted that improved patient outcomes will come
from novel treatment strategies resulting from an improved understanding of
the biology of the microenvironment in AML.
Bone marrow stromal cells (BMSCs) are an instrumental component of the
AML microenvironment and have been shown to play a role in its survival and
evasion from apoptosis. The aims of my PhD research were to investigate
novel interactions between AML cells and BMSCs which benefit AML survival
in vitro and in vivo. Here, I identified an AML-BMSC feedback loop where AMLderived
macrophage migration inhibitory factor (MIF) stimulated BMSCs,
through the activation of stromal protein kinase C, to secrete the pro-survival
cytokine interleukin-8 (IL-8). Moreover, I found that MIF expression in the AML
compartment is regulated by hypoxia through stabilisation of HIF1α. Inhibition
of HIF1α or MIF significantly enhanced survival and reduced tumour burden in
vivo. Finally, I showed that AML cells induce senescence in BSMCs through
upregulation of the cyclin-dependent kinase inhibitor, p16. Deletion of p16 in
BMSCs reduced AML survival in co-culture models.
In summary, the data presented in this thesis provide important insights into
the AML-BMSC interactions and could facilitate the development of future
therapeutic approaches in the treatment of AML.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Stacey Armes
Date Deposited: 22 Mar 2018 16:57
Last Modified: 22 Mar 2018 16:57


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