Mechanisms of radiation leukaemogenesis, characterisation of haematopoietic stem cells and modulation of risk


Haematopoietic bone marrow cells are amongst the most sensitive to ionising radiation (IR), initially resulting in cell death or genotoxicity that may later lead to leukaemia development, most frequently Acute Myeloid Leukaemia (AML). The target cells for radiation-induced Acute Myeloid Leukaemia (rAML) are believed to lie in the haematopoietic stem and progenitor cell (HSPC) compartment. Using the inbred strain CBA/Ca as a murine model of rAML, progress has been made in understanding the underlying mechanisms, characterisation of target cell population and responses to IR. Complex regulatory systems maintain haematopoietic homeostasis which may act to modulate the risk of rAML. However, little is currently known about the role of metabolic factors and diet in these regulatory systems and modification of the risk of AML development.
This study characterises cellular proliferative and clonogenic potential as well as metabolic changes within murine HSPCs under oxidative stress and X-ray exposure. Ambient oxygen (normoxia; 20.8% O2) levels were found to increase irradiated HSPC-stress, stimulating proliferative activity compared to low oxygen (3% O2) levels. IR exposure has a negative influence on the proliferative capability of HSPCs in a dose-dependent manner (0–2 Gy) and this is more pronounced under a normoxic state. One Gy x-irradiated HSPCs cultured under normoxic conditions displayed a significant increase in oxygen consumption compared to those cultured under low O2 conditions and to unirradiated HSPCs. Furthermore, mitochondrial analyses revealed a significant increase in mitochondrial DNA (mtDNA) content, mitochondrial mass, and membrane potential in a dose-dependent manner under normoxic conditions. Our results demonstrate that both IR and normoxia act as stressors for HSPCs, leading to significant metabolic deregulation and mitochondrial dysfunctionality which may affect long term risks such as leukaemia.
Diet can greatly impact health, while caloric restriction and fasting regimens possess conferring potential benefits for disease prevention and longevity. However, comprehensive investigations are required to elucidate the precise effects of distinct dietary protocols (e.g., caloric restriction, fasting, amino acid depletion), on haematopoietic malignancies including radiation-induced acute myeloid leukaemia. Our research highlights a remarkable reduction in the proliferative capacity of short-term primary HSCs when subjected to dietary valine depletion, displaying metabolically less active phenotype. Moreover, employing an in vivo fasting regimen using a CBA mouse model of rAML, we observe a significant reduction in mCherry loss, particularly in the initial stages following radiation exposure. This study provides a fundamental platform for further investigation into the intricate interplay between dietary modifications and the progression of radiation-induced acute myeloid leukaemia. Despite the current inherent limitations within the available dataset, the implementation of dietary interventions holds a great potential and may lower the risk of long-term complications in cancer patients.

Keywords: haematopoietic stem and progenitor cell
ionising radiation
metabolism
alternate fasting
acute myeloid leukaemia
radiation leukaemogenesis
diet
reactive oxygen species
oxidative stress
mitochondrial dysfunction
hypoxia
Advisor: Badie , C
Hill, M