| dc.description.abstract | Haematopoiesis is a life-long process of blood cell production that occurs through strictly regulated self-renewal, proliferation, and differentiation of haematopoietic stem cells (HSCs) in hypoxic microenvironment of the bone marrow niche. Accumulation of clonal mutations, that give mutated haematopoietic stem and progenitor cells (HSPCs) proliferative advantage, and subsequent acquisition of driver mutations lead to development of Acute Myeloid Leukaemia (AML)-initiating leukaemic stem cells (LSCs). Standard chemotherapies efficiently target AML blasts; however, they frequently fail to eradicate the chemotherapy resistant LSCs, leading to disease relapse. Thus, exposing biological vulnerabilities of LSCs is of great therapeutic interest. 2-oxoglutarate (2OG)-dependent oxygenases (2OGXs) are superfamily of enzymes involved in numerous important biological processes including hypoxia sensing, epigenetic regulation, or cellular metabolism. Moreover, the function of 2OGXs is controlled by tricarboxylic acid (TCA) cycle metabolites. However, the role of many 2OGXs and their metabolic regulation in normal haematopoiesis and leukemogenesis is poorly understood. This thesis shows that member of 2OGXs, Jumonji domain-containing protein 6 (JMJD6), is a critical regulator of HSCs during steady-state haematopoiesis, upon haematopoietic injury, and serial transplantation. JMJD6 controls the HSC function by suppressing the oxidative phosphorylation (OXPHOS) which prevents aberrant production of toxic reactive oxygen species (ROS). Moreover, this thesis reveals that JMJD6 is not required for leukaemic transformation, LSCs development, and AML propagation in models that involve the histone lysine methyltransferase 2A (KMT2A aka MLL) rearrangement. This thesis also finds that stabilisation of Hypoxia Inducible Factor (HIF-) through pharmacological inhibition of Prolyl Hydroxylase Domains (PHDs) is a promising therapeutic strategy to target LSCs in AML, without serious adverse effects. Furthermore, PHD inhibition significantly potentiates the efficacy of B-Cell Lymphoma (BCL-2) inhibitor venetoclax. Lastly, this thesis shows that Diroxymel fumarate (DRF) potently targets AML in vitro, and substantially increases the efficacy of venetoclax in vivo; proposing the utilisation of fumarate esters for AML treatment. | en_US |
