Penetrant PKCβ mutation in ATLL displays a mixed gain-of-function

Mutations in the T-cell receptor signalling pathway have been identified in patients with adult T-cell leukaemia/lymphoma (ATLL) and one of the most frequently observed targets of these mutations is protein kinase C beta (PKCβ). Here, we have characterised the most frequent mutation in PKCβ (D427N), addressing the issue of gain/loss of function, neomorphic change and assessing the impact of mutation in vivo, in cells, biochemically and structurally. It is concluded that this mutation is a gain-of-function, activating mutation that confers an altered substrate specificity on this protein kinase. In a constitutive knock-in mouse model, this activated allele induces splenomegaly associated with extramedullary haematopoiesis. Pharmacologically, the D427N mutant protein displays poor sensitivity to established PKCβ inhibitors, necessitating the development of bespoke therapeutics for any ATLL intervention through this target. Such efforts could be guided by the availability of the D427N mutant-ruboxistaurin structure presented here.