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

• Main Author: Abdul-Aziz, Amina
• Published: University of East Anglia 2017
• Subjects: 610
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.738662

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.