Tfh Lymphoma: Analysis of a RHOA Mutation & Establishment of a Pre-Clinical Model
thesisposted on 13.02.2019, 14:52 by Rebecca L. Allchin
T cell lymphoma is a rare haematological cancer but represents an area of unmet need with little improvement in patient outcomes over the last 20 years. However, recently there has been an increase in the understanding of T cell biology and development of a subtype of T cell lymphoma known as Tfh lymphoma. This has been associated with the detection of recurrent mutations which occur in Tfh lymphoma including mutations found in RHOA. Here I show that the expression of RHOA carrying the mutations found in Tfh lymphoma samples is lower than the WT RHOA protein, and that these mutated proteins have reduced activity. The combination of this work and other recently published work suggests that the mutated RHOA is found at lower levels which may be due to protein instability. Although it has reduced GTP binding ability the mutated protein may activate other pathways leading to its role in lymphomagenesis. Due to the lack of preclinical models of Tfh lymphoma I have further characterised a T cell lymphoma model initially described by Ellyard et al showing that this represents a model of a genetically diverse lymphoma which occurs on an immunocompetent background. I demonstrate the use of Magnetic Resonance Imaging (MRI) to assess the response of the lymphoma to treatment. I demonstrate the utility of MRI to monitor changes in lymph node size showing this to be a useful tool in assessment of treatment effects. Subsequently I show the effect of ITK inhibition with ibrutinib on the T cell lymphoma in this model. Ibrutinib shows a mixed response in this model and no biomarkers of response were found.