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Asparaginase (ASNase) treatment results in synthesis of some factors such as ATF4. The eIF2-ATF4 pathway is essential for cell survival during amino acid starvation conditions. Activation of the AAR in liver requires the eIF2 kinase called general control nonderepressible 2 kinase (GCN2). To what extent activation of the GCN2-eIF2-AAR is mediated by ATF4 is unknown. Our objective and hypothesis are addressed in our aim to describe the liver response to ASNase in mice deleted for Atf4. RNA sequencing alongside complementary biochemical approaches were performed in the livers of mice treated with eight daily injections of ASNase or saline excipient. Cellular pathways examined in detail included the AAR. We discovered that global hepatic gene expression patterns in Atf4 knockout mice overlapped with Gcn2 knockout mice. Shared hepatic pathways or processes altered during ASNase included mTOR signaling, and xenobiotic metabolism. On the other hand, loss of Atf4 during ASNase uniquely altered gene expression signatures reflecting signaling via eIF2 and ER stress. This research provides insight into the importance of genetic background of patients in choosing ASNase as a treatment.

General Control Nonderepressible 2 and ATF4 Direct Liver Genes during Asparaginase Treatment in Mice