Multi-omic analysis of human poor risk acute myeloid leukaemia to replace xenotransplantation assays and expand leukaemic stem cells

Cancer is swiftly becoming one of the leading cause of death in western populations, and it is estimated that 1in2 people born in the U.K. after 1960 will be diagnosed with cancer during their lifetime. Approximately 375,000 new cases of cancer are diagnosed in the U.K. every year (>1,000 per day) and only 50% of those are expected to survive. That equates to more than 450 cancer related deaths per day. Demonstrating the critical need for a better understanding of the underlying biology of cancer and development of new effective therapies. Acute myeloid leukaemia (AML) is a blood cancer with a very poor prognosis. Treatment options have remained largely unchanged in the last 30 years, with good initial response to therapy, but high rates of relapse and very poor overall survival. One of the key problems with current therapy is the inability to deplete cells at the apex of the disease, so called leukaemic stem cells (LSCs). These cells are highly resistant to therapy and are the origins of relapse and ultimately the root cause of poor prognosis in AML. AML is a heterogeneous disease that requires multimodal investigation to better understand the underlying biology and reveal novel targets. The gold standard for proving functionality in human AML and studying leukaemic stem cells (LSCs) in laboratory practice is testing patient derived xenografts (PDX) models. Yet there are many major issues associated with PDX, most importantly that the majority of patient AML samples do not engraft and few individual samples can be used from large cohorts. Therefore, developing new ways to reduce large-scale PDX screening, replace upfront PDX with non-animal testing, and revealing new biological mechanisms for growing AML ex vivo has major potential to change the way we study human AML biology. In this PhD we will use a large array of AML multi-omic datasets matched to PDX potential to deconvolute the key factors that would predict the ability of patient samples to engraft immunodeficient mice in an effort to replace large-scale PDX screening. The PhD student will use the most promising biomarkers, mechanisms and predictive omic types to understand the key requirements to maintain and expand AML LSCs ex vivo to replace the need for PDX in studying LSC biology and testing new therapeutic targets. Ultimately this PhD will aim to make major changes to the way we approach studying human AML in laboratory settings.