Abstract A012: Exploring the role of adaptive amino acid responses in Ras-driven leukemia progression and therapy

Abstract Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, affecting the lymphoid cells of both B and T lineages. Most ALL cells are auxotrophic for asparagine, a nonessential amino acid for protein synthesis, due to the low expression of asparagine synthetase (ASNS), a rate limiting enzyme for de novo biosynthesis of asparagine. As a result, standard ALL treatment takes advantage of this vulnerability by giving patients L-asparaginase, a bacterial enzyme that depletes the circulating asparagine. However, previous work from our lab and others have shown that some ALL cells become resistance to L-asparaginase treatment through the induction of ASNS expression. Mechanistically, amino acid starvation actives the general control nonderepressible 2 (GCN2) kinase, leading to the accumulation of ATF4 transcriptional factor. ATF4, in turn, is recruited to the promoter of the ASNS gene to activate its transcription. However, the role of GCN2 kinase in the process of leukemogenesis under nutrient limiting environment has not been established. In this study, our goal is to use a mouse model of T-ALL driven by mutant KRas to determine the role of GCN2 in leukemogenesis and the therapeutic response to L-asparaginase treatment. Citation Format: Ji Zhang, Rodney Claude, Sankalp Srivastava, Sandeep Batra, Minghua Zhong, Utpal Dave, Ronald C. Wek. Exploring the role of adaptive amino acid responses in Ras-driven leukemia progression and therapy [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A012.