T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive blood cancer that most frequency occurs in children. While a growing number of treatments have led to improved survival, morbidity remains high, and prognosis is poor for those who fail to achieve remission or with disease relapse. There is thus a critical need to understand the underlying causes of T-ALL to improve detection and enable the development of more effective treatments. T-ALL arises from the transformation of T cell precursors (known as thymocytes) in the thymus. Research efforts have mostly focused on identifying driver gene mutations within the malignancy itself, but these typically accumulate later in the disease process and do not appear to be the underlying cause of the disease. Instead, we process that it is defects in the thymic microenvironment that could be initiator disease in the first place and this project will explore this hypothesis.
This project will employ mouse models of T-ALL and will investigate the interaction of the thymic microenvironment with thymocytes. Techniques to be employed include the application of high dimensional flow cytometry, single cell RNA sequencing, in vitro function assays and transgenesis. The goal will be to demonstrate that abnormalities in the thymic microenvironment precedes thymocyte transformation and to elucidate the mechanisms involved.
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