Abstract 2095: DEPTOR is a direct NOTCH1 target that regulates proliferation, metabolism and glucocorticoid resistance in T cell leukemia

Abstract

Abstract DEP-Domain Containing mTOR-Interacting Protein (DEPTOR) is frequently overexpressed in multiple myelomas and required for cell survival. However, its implications in other hematological malignancies and the precise mechanisms of regulation remain largely undefined. Here, we systematically analyzed DEPTOR expression in human acute lymphoblastic leukemia (ALL), a hematological malignancy accounting for 80% of pediatric leukemia. Whereas substantially inhibited in B-ALLs, unexpectedly, expression of DEPTOR is significantly elevated in a subset of T-ALLs where NOTCH1 is aberrantly activated. Mechanistically, we show DEPTOR expression is dependent on NOTCH signaling in T-ALL cell lines and primary specimens, and demonstrate NOTCH1 directly binds to and activates human DEPTOR promoter. DEPTOR depletion in T-ALL cells abolishes proliferation, attenuates glucose metabolism, enhances apoptosis and sensitizes resistant cells to γ-secretase inhibitor or dexamethasone treatments. Conversely, ectopically expressed DEPTOR promotes proliferation and aerobic glycolysis, and confers dexamethasone resistance. DEPTOR functions through AKT-dependent mechanisms to sustain cell proliferation and drug resistance, while the AKT-independent roles of DEPTOR appear to promote glucose metabolism. We therefore define a novel mechanism that, in addition to the previously reported HES1/PTEN-mediated regulation of AKT, NOTCH1 alternatively activates AKT through inducing the downstream target gene DEPTOR. Our findings thereby highlight DEPTOR as a critical mediator in leukemogenesis and suggest DEPTOR expression may serve as a potential biomarker predicting glucocorticoid resistance and targeting DEPTOR may achieve better therapeutic benefits. Citation Format: Yufeng Hu, Hexiu Su, Qi Ye, Zhaojing Wang, Liang Huang, Qian Wang, Shuangyou Liu, Suning Chen, Jianfeng Zhou, Peng Li, Guoliang Qing, Hudan Liu. DEPTOR is a direct NOTCH1 target that regulates proliferation, metabolism and glucocorticoid resistance in T cell leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2095. doi:10.1158/1538-7445.AM2015-2095