Brown, Sophie Jane Livermore; (2023) The effects of a penetrant mutation in Adult T-cell Leukaemia on the properties of Protein Kinase C β. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Adult T-cell leukaemia/lymphoma (ATL), caused by human T-cell leukaemia virus type 1, is an aggressive malignancy with a poor prognosis. ATL leukaemogenesis occurs over decades and involves many viral, epigenetic and genetic events; these genetic events include frequent mutations in components of the signalling pathway from the T-cell receptor to NF-kB. The D427N mutation in Protein Kinase C β (PKCβ) is a penetrant mutation which occurs in almost a quarter of patients and, whilst PKCβ is known to function downstream of the B-cell receptor to activate NF-kB in B-cells, a previous study provides evidence that D427N is a gain-of-function mutation which increases NF-kB activity in T-cells. It has also been suggested that D427N could destabilise PKCβ (loss-of-function) or, due to the predicted role of D427 in substrate binding, that it could be a neomorphic (change-of-function) mutation which switches PKCβ substrate specificity. This thesis aimed to determine the effects of the D427N mutation on the properties of PKCβ, evaluate how this contributes to the leukaemogenesis of ATL in a mouse model and assess whether inhibiting D427N PKCβ activity has therapeutic potential. The D427N mutation did not destabilise PKCβ but induced a more open conformation which partially activated the kinase under basal conditions. Studies of D427N PKCβ substrate specificity demonstrated significantly different activities towards substrates in vitro and suggest D427N could have neomorphic functions by altering the pattern of substrate phosphorylation in cells. A mouse model heterozygous for D427N PKCβ developed increased extramedullary haematopoiesis in the spleen. These findings support the inhibition of D427N PKCβ activity as a potential treatment for ATL, but the results also showed that available PKC inhibitors were less effective towards D427N PKCβ. A crystal structure of D427N PKCβ bound to an inhibitor is presented, which could inform the development of more potent and specific inhibitors in future.

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