Acute myeloid leukaemia differentiation therapy response and relapse

Acute myeloid leukaemia (AML) is caused by accumulated oncogenic mutations in white blood cell progenitors that lock them into an immature self-renewing state. Approximately 1000 Australians are diagnosed with AML each year, but less than one third will survive beyond 5 years. Most AML patients are treated with cytotoxic chemotherapy that kills immature leukaemia cells but also normal cells, with dose-limiting side effects and high relapse rates. In contrast to chemotherapy, AML differentiation therapy triggers leukaemia maturation leading to the subsequent clearance of mature leukaemia-derived cells. In principle AML differentiation therapy is preferable to chemotherapy because it avoids widespread genotoxic cell death. Instead, triggering leukaemia maturation engages highly efficient clearance mechanisms that normally turn over 100 billion mature myeloid cells (predominantly neutrophils) daily. Several new AML differentiation therapies have recently entered the clinic. Unfortunately, while many initially yield robust clinical responses, relapse remains almost inevitable. Surprisingly little is known about the phenotype and fate of mature leukaemia-derived cells in patients on differentiation therapy, because these cells are often indistinguishable from normal mature myeloid cells. The cellular origin of AML relapse following differentiation therapy also remains poorly understood, and preventing relapse remains a major clinical challenge. Recent work from our lab has identified new concepts central to differentiation therapy response and relapse. In 2019 (McKenzie*, Ghisi*, Oxley* et al, Cell Stem Cell) we demonstrated for the first time that mature AML-derived cells can regain leukaemogenic activity by undergoing de-differentiation, challenging the traditional cancer stem cell model of this disease. By tracking the in vivo fate of leukaemia cells following differentiation therapy in mouse AML models, more recently we have shown that specific lineages of mature leukaemia-derived cells can seed disease relapse (Ngo et al, Nature Communications 2021). This project will use molecular biology, genetics, and cell biology techniques to interrogate high resolution mouse and human models of AML differentiation therapy. It will examine mechanisms of mature leukaemia cell clearance, persistence, and acquisition of resistance that drives relapse. It will also test novel combination therapies rationally designed to prevent relapse. Our lab has generated multiple mouse models of AML differentiation therapy that can be reversibly toggled between immature and mature states. This genetic switching system provides a powerful platform for functionally interrogating genes involved in AML self-renewal, therapy response, and residual disease states following therapy. We will systematically address these processes using RNAi and CRISPR/Cas9 in cultured leukaemia cells and following transplant into mice, and examine strategies for preventing relapse following differentiation therapy. Ultimately this project aims to raise cure rates for AML patients.