NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap(4)A) and Down-Regulates Immune Response and Cancer Promotion Genes

Marriott, Andrew S.; Vasieva, Olga; Fang, Yongxiang; Copeland, Nikki A.; McLennan, Alexander G.; Jones, Nigel J.

In order to determine whether transcriptional regulation by Ap 4 A is confined to relatively few genes or is more widespread, we have analysed the transcriptome of a knockout derivative of the KBM-7 chronic myeloid leukaemia (CML) cell line [37] in which the intracellular level of Ap 4 A has been increased 175-fold by disruption of the NUDT2 gene (KBM-7-NuKO, referred to hereafter as NuKO). These cells show profound changes in gene expression compared to the parent KBM-7 cell line with a total of 6288 significantly differentially expressed genes (DEGs) identified. Ingenuity 1 Pathway Analysis was used to highlight the gene networks and metabolic and signaling pathways affected, revealing down-regulation of interferon, inflammatory and innate immune responses and up-regulation of processes involving MHC class II antigens. In addition, many of the most strongly affected genes have roles in promoting cancer metastasis and invasion, suggesting that NUDT2 may offer a novel, pleiotropic target for cancer chemotherapy.