Establishing the mechanism for RUVBL2 essentiality in acute myeloid leukaemia

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Despite remarkable advances in the treatment of common leukaemia in children, some types of this disease, such as acute myeloid leukaemia (AML), are still difficult to treat. Current therapy fails to cure 1 in 3 children diagnosed with AML, and over half of adult patients, indicating an urgent need for new and improved treatments. There is general consensus in leukaemia research that advances likely to result in such new therapies rely on achieving a greater understanding of the molecular basis of the disease. Our group studies how cancer genes hijack normal cellular pathways to promote conversion of normal blood cells into leukaemia. We and others have shown that the molecule c-MYB mediates cancer gene function in most AML types, ensuring that AML cells continuously divide, producing copies of themselves, and that they do not differentiate into mature blood cells. In AML patients, this results in the replacement of normal blood cells with non-functional leukaemia cells, leading to catastrophic deficiencies in tissue oxygen delivery, poor blood clotting and susceptibility to infection. However, targeting c-MYB itself is problematical, mainly due to its requirement for normal blood cell development. We recently uncovered a pathway operating in AML cells, in which the protein RUVBL2 controls the activity of c-MYB, ensuring it blocks differentiation of AML cells. Although inhibition of RUVBL2 resulted in the death of AML cells, it had little impact on normal blood cell development. This suggests that therapies targeting this protein may be effective and relatively non-toxic. This project aims to characterise how RUVBL2 controls c-MYB and to discover what parts of RUVBL2 are necessary for this control. We will then examine the effects of interfering with control of c-MYB function by RUVBL2 on AML cells using experimental models of the disease. We will use the results from this project to determine how effective new therapies that block RUVBL2 function are likely to be and envisage using this information for future development of these therapies in AML.