Genetic and epigenetic consequences of radiation exposure in human and mouse leukaemogenesis

Abstract

Ionising radiation (IR) is a well-known carcinogen. For example, there is a dose-dependent increase of cancer incidence seen in the atomic bomb survivors in Japan. Acute Myeloid Leukaemia (AML) is one of the most common cancers to occur in humans following IR exposure. It can also be induced by radiotherapy treatment - so called therapy-related or secondary AML. Although widely studied, the underlying mechanisms of radiation-induced AML (rAML) are yet to be fully characterised. The main purpose of this research is to examine the target cells for rAML development, the hematopoietic stem and progenitor cells (HSPC). Previous studies have allowed classification of HSPC into three sub groups based on their repopulating abilities (long term HSC, short term HSC and haematopoietic progenitor cells (HPC)). We aim to characterise the response and sensitivity of these sub-populations of HSPC to IR. Recent work has focused on analysing the gene expression profiles of these sub-populations. We will expand on this by studying modifications of gene expression and methylation changes in these sub-populations following ionising radiation exposure in order to improve our understanding of the mechanisms of radiation-induced leukaemogenesis. Mouse and human samples of rAML will be used during this project with the aim to characterise the molecular mechanisms of rAML induction, assessing the suitability of the mouse model for humans and making for a first time an interspecies comparison analysis.