Novel tumor suppressor roles for GZMA and RASGRP1 in dissemination of both Theileria annulata-transformed macrophages and human B-lymphoma cells

Abstract

AbstractTheileria annulata is a tick-transmitted apicomplexan parasite that infects and transforms bovine leukocytes into disseminating tumors that cause a disease called tropical theileriosis. Using comparative transcriptomics we identified genes transcriptionally perturbed during Theileria-induced 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 knock-down. Knocking down 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-lymphoma cells 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-lymphoma cells that overexpress GZMA and RASGRP1. Our results provide evidence that GZMA and RASGRP1 have a novel tumor suppressor function in both T. annulata-infected bovine host cells and in human B-lymphomas.SummaryWe compared the transcriptomes of Theileria annulata transformed B-lymphocytes to 934 human cancer cell lines and provide functional evidence for shared tumor suppressor roles for GZMA and RASGRP1 in controlling the dissemination phenotype of both human B lymphomas and Theileria-transformed leukocytes.