Role of Wilms Tumour 1 Mutations in Acute Myeloid Leukaemia

Acute Myeloid Leukaemia (AML) is a blood disorder of later life that arises from the accumulation of genetic damage (mutation) in the blood stem cells. Mutations in these cells results in the accumulation of immature cells called myeloblasts in the bone marrow and peripheral blood of patients to the exclusion of healthy cells. This compromises the body s own defences to fight infection. Despite improvements in chemotherapy two thirds of patients with AML will die from their disease. Our group has set out to identify and characterise the mutations that give rise to AML as a means of directly targeting these rogue stem cells. Our recent studies of the Wilms tumour 1 (WT1) gene mutations identified a particularly poorly performing patient group. Curiously and in contrast to Wilms tumour, a paediatric kidney cancer, from which the gene takes its name, its role in leukaemia is only speculative. We now want to decipher how mutant WT1 contributes to the onset of AML, its interaction with other mutational events and the mechanisms by which it confers poor outcome and drug resistance on the leukaemic cells. We have brought together experts in the fields clinical and basic research haematology and leaders in the field of Wilms tumour research to address these questions and to open the door to the better clinical management of this disease in the future.

Our preliminary studies show that mutations in Wilms Tumour 1 (WT1) occur in 10% of AMLs with normal karyotype and are associated with a failure to respond to standard induction chemotherapy. Wild-type WT1 has been proposed to act both as an enhancer of cellular quiescence in haematopoeitic stem cells (HSC) and later as an inducer of cellular differentiation in committed precursors. Hence, mutation of WT1 may promote stem cell proliferation and induce a block in differentiation, the hallmarks of the 2-step hypothesis for the development of AML. The identification of the specific pathways deregulated as a result of mutation in WT1 are therefore likely to represent attractive targets for reversing the affects of mutation and the testing of new anti-leukaemic agents. The implementation of WT1 mutation status into clinical practice is however dependent on confirming the prognostic value and an understanding of its mode of action within the HSC and myeloblasts. We will set out to (i) determine the prognostic implications of WT1 mutation in normal and other karyotypic AML risk groups by correlating mutation status of the gene in patients treated as part of the MRC Clinical AML trials patient cohorts with clinical parameters (ii) make use of gene expression profiles to select survival or differentiation pathways through which the mutant protein exerts its function and to test for deregulation of these pathways using in vitro (WT wild-type and WT1 mutated cell lines) and in vivo (Denys Drash syndrome (DDS) and cord blood mutation models and (iii) to examine by use of the DDS mouse and a human cord blood model the consequences of WT1 mutation on HSC function alone or in combination with other mutational events. These studies will lead to a greater understanding of the biological consequences and role of WT1 in leukaemia which along with its current clinical application in immunotherapeutic approaches and minimal residual disease strategies have the potential to impact positively on clinical practice and the delivery of an improvement in the overall survival of patients with AML.