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

Theileria annulata is 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 during Theileria‐induced leukocyte transformation. Dataset comparisons highlighted a small set of genes associated with Theileria‐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 of GZMA and RASGRP1 in attenuated macrophages led to a regain in their dissemination in Rag2/γC mice confirming their role as dissemination suppressors in vivo. We further evaluated the roles of GZMA and RASGRP1 in human B lymphomas by comparing the transcriptome of 934 human cancer cell lines to that of Theileria‐transformed bovine host cells. We confirmed dampened dissemination potential of human B lymphomas that overexpress GZMA and RASGRP1. Our results provide evidence that GZMA and RASGRP1 have a novel tumour suppressor function in both T. annulata‐infected bovine host leukocytes and in human B lymphomas.