Jim Neil - Overview

The central research theme of the Molecular Oncology Group is the aetiology of haemopoietic cancers. The development of cancer is a multistep process in which cells lose normal growth controls through a series of mutations affecting key regulatory genes. The main focus of the group is to identify the genes involved in this process and to understand how different types of oncogenic lesions can collaborate to transform a normal cell into a highly malignant one. Using molecular and cellular techniques, the general approach is to model the gene interactions which underlie neoplastic disease with the intention of characterising the phenotypic changes that act in concert to induce cancer. The identification of the relevant target genes and a more complete understanding of genetic complementation in cancer may lead to improved genotypic classification of human cancers and the development of rational approaches to therapy. In this endeavour, we have made extensive use of retroviral mutagenesis as a means of identifying novel target genes. These viruses, by virtue of integration into the host cell genome, can either activate or inactivate host cell genes critical to growth regulation and/or cell survival. Many of the genes known to be important in human cancer were first identified in this way, including Myc, Ras and Abl.

A major focus of our current work is the core binding factor family, a set of three mammalian transcription factors encoded by the RUNX genes (previously known as AML, CBFA, or PEBP2α) which regulate the activity of many genes with key roles in growth control and differentiation. The RUNX1 gene is one of the most common targets for mutations in human leukaemias, participating in at least ten different chromosomal translocations in AML and childhood ALL, and displaying somatic mutations in a proportion of cases of AML. Our studies have shown that any of the three murine RUNX genes can be activated to collaborate with Myc in the genesis of T-cell lymphoma, despite their markedly different patterns of expression and functional roles in normal development. We are currently exploring the consequences of RUNX over-expression in vivo and in vitro, with the aims of elucidating the selective advantage that these genes confer on the tumour cell and the downstream pathways through which they operate. Longer term goals are to explore the involvement of RUNX gene deregulation in solid tumours and the use of transgenic models in the development and testing of novel therapeutic strategies.