Development of anti-LMO2 drugs for treatment of T cell leukaemia

Dysregulation of the LM02 proto-oncogene as a result of reciprocal chromosomal translocation involving the T-cell receptor gene loci, is a hallmark of some cases of T-cell acute lymphoblastic leukaemia (T-ALLL an aggressive subset of leukaemia. Aberrant expression of the gene is also seen in a significant proportion of cases. LM02 activation following retroviral insertion is further directly implicated in the pathogenesis of T-ALL that occurred in two gene therapy trials, while T-cell overexpression of the gene can be used to model the disease in mice. These existing models have been developed within, towards the live imaging of tumours; and to study the effect of an additional genetic lesion, with the goal of reducing the latency to tumour development. The LM02 protein is a component of multi-protein DNA-binding complexes with a role in cell fate decisions. Protein-protein interactions between LM02 and partners, in particular TAll, are targets for drug development, though this is a challenging therapeutic area. Previous isolation of an intracellular antibody fragment able to bind i to LM02 and inhibit important biological functions and pre-clinical tumour formation, is an important advance. However, in the absence of robust platforms for the efficient delivery of such a macromolecule, it is argued that the optimum therapeutic strategy is to discover small molecules that can mimic the interaction with LM02. To this end, this study contributes additional information about the interaction surface of this scFv, and applies the antibody technology to study of the dynamic interactions between LM02 and its protein partners. Both would be greatly strengthened by a structural solution of the scFv-LM02 complex. Though further work is required in each of the contributing areas before the goal of anti-LM02 drugs is realised, ultimately the ability to target multiple cellular pathways is desirable, and an approach to studying this in model systems has been developed.EThOS - Electronic Theses Online ServiceGBUnited Kingdo