Within a highly successful research environment, we will develop a state-of the-art high throughput functional in vivo oncogenicity assay, using mouse bone marrow transplant models of leukaemia to conclusively identify the important genetic changes involved in the development and progression of cancer. This study will focus on B-lineage acute lymphoblastic leukaemia (ALL), for which there is a wealth of knowledge on the biology of the disease. Our aim will be to differentiate between driver and passenger genes, when other techniques have implicated large numbers of candidates. Initial areas of focus will be 1) to determine the gene(s) involved in patients with the poor risk subtype of ALL, iAMP21, so that these may be specifically targeted by molecular therapy. This is important to reduce the high level of toxic treatment required to prevent relapse in these patients; 2) to definitively identify tumour suppressor genes within the deleted region of chromosome 6. Patients with this abnormality comprise a high proportion of ALL and non Hodgkin s lymphoma (NHL), particularly childhood T-lineage NHL, where it is linked to a poor prognosis; 3) to identify and characterise those genes involved in drug resistance leading to relapse. Candidate tumour suppressor genes associated with relapse have already been implicated. Comprehensive sequencing of further samples will identify additional mutated genes. The ultimate aim is to determine the clinical relevance of these abnormalities and develop molecular genetic assays suitable for routine clinical detection, with a view to validating their role as molecular targets for therapy; a particular strength of my group. In the future this methodology will be extended to the detection of genes in other haematological malignancies.