Deletion of GCN2 affects whole body and tissue response to asparaginase

Abstract

Asparaginase (ASNase) treatment results in the synthesis of some factors such as activating-transcription-factor-4 (ATF4). The eIF2-ATF4 pathway is essential for cell survival during amino acid starvation conditions. This requires the eukaryotic-initiation-factor-2 (eIF2) kinase called general control nonderepressible 2 kinase (GCN2). Our objective and hypothesis are addressed in our aim to describe the liver response to ASNase in mice deleted for Gcn2 and Atf4 and either treated with phosphate buffered saline (PBS) or asparaginase (ASNase) for 8 days. We found that deletion of Gcn2 and/ or Atf4 affect body weight and fat and lean content. The results showed that Atf4-/- mice had significantly less fat mass than WT and Gcn2-/- mice even before the startup of the study. Also, WT mice experienced minimal change in body weight and body composition, but Atf4-/- and Gcn2-/- mice both lost substantial amounts of body weight and body fat without altering lean mass. Moreover, Gcn2-/- mice showed high significant increment in liver and pancreas weight when treated with ASNase compared to the other groups. Lastly, spleen weight was significantly lower in all treated groups, except Atf4 null mice, compared to their own control groups. In conclusion, this research provides insight into the importance of the genetic background of patients in choosing ASNase as a treatment.