GPS2 confers l-asparaginase resistance in acute lymphoblastic leukemia cells through ATF4/ASNS axis

l-asparaginase (l-ASP) is an important chemotherapeutic agent used in the treatment of pediatric acute lymphoblastic leukemia (ALL). However, resistance to l-ASP is an unfavorable prognostic factor, and the mechanism underlying l-ASP resistance is not fully understood. Here, we show that activation of the activating transcription factor 4 (ATF4) and induced expression of downstream target asparagine synthetase (ASNS) play a pivotal role in l-ASP resistance of ALL cells. In addition, the G protein pathway suppressor 2 (GPS2) binds to ATF4 and stabilizes ATF4 protein. Mechanistically, GPS2 inhibits ubiquitin-proteasome degradation of ATF4 through impairing the interaction between ATF4 and beta-transducin repeat-containing E3 ubiquitin protein ligase (BTRC), an E3 ligase that triggers proteasomal degradation of ATF4. Moreover, GPS2 knockdown sensitizes ALL cells to l-ASP treatment via repressing the ATF4/ASNS axis in vitro and increases l-ASP efficacy against xenografted ALL tumors in vivo. Taken together, these findings demonstrate that GPS2 positively regulates the ATF4/ASNS axis to confer l-ASP resistance in ALL cells, suggesting a therapeutic potential of targeting this pathway to overcome l-ASP resistance.