Novel tumour suppressor roles for GZMA and RASGRP1 in Theileria annulata-transformed macrophages and human B-lymphoma cells.

Theileria annulatais a tick-transmitted apicomplexan parasite that infects and transforms bovine leukocytes into disseminating tumours that cause a disease called tropical theileriosis. Using comparative transcriptomics we identified genes transcriptionally perturbed duringTheileria-induced leukocyte transformation. Dataset comparisons highlighted a small set of genes associated withTheileria-transformed leukocyte dissemination. The roles of Granzyme A (GZMA) and RAS guanyl-releasing protein 1 (RASGRP1) were verified by CRISPR/Cas9-mediated knockdown. Knocking down expression ofGZMAandRASGRP1in attenuated macrophages led to a regain in their dissemination in Rag2/gamma C mice confirming their role as dissemination suppressors in vivo. We further evaluated the roles ofGZMAandRASGRP1in human B lymphomas by comparing the transcriptome of 934 human cancer cell lines to that ofTheileria-transformed bovine host cells. We confirmed dampened dissemination potential of human B lymphomas that overexpressGZMAandRASGRP1. Our results provide evidence thatGZMAandRASGRP1have a novel tumour suppressor function in bothT. annulata-infected bovine host leukocytes and in human B lymphomas.