Aberrant activation of NOTCH1 signaling plays a vital role in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL). Yet the molecular events downstream of NOTCH1 that drive T-cell leukemogenesis remain incompletely understood. Starting from genome-wide gene-expression profiling to seek important NOTCH1 transcriptional targets, we identified DEP-domain containing mTOR-interacting protein (DEPTOR), which was previously shown to be important in multiple myeloma but remains functionally unclear in other hematological malignancies. Mechanistically, we demonstrated NOTCH1 directly bound to and activated the human DEPTOR promoter in T-ALL cells. DEPTOR depletion abolished cellular proliferation, attenuated glycolytic metabolism and enhanced cell death, while ectopically expressed DEPTOR significantly promoted cell growth and glycolysis. We further showed that DEPTOR depletion inhibited while its overexpression enhanced AKT activation in T-ALL cells. Importantly, AKT inhibition completely abrogated DEPTOR-mediated cell growth advantages. Moreover, DEPTOR depletion in a human T-ALL xenograft model significantly delayed T-ALL onset and caused a substantial decrease of AKT activation in leukemic blasts. We thus reveal a novel mechanism involved in NOTCH1-driven leukemogenesis, identifying the transcriptional control of DEPTOR and its regulation of AKT as additional key elements of the leukemogenic program activated by NOTCH1.
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We thank Drs Warren Pear (University of Pennsylvania, Philadelphia, PA, US), Hongbing Shu and Zan Huang (Wuhan University, Wuhan, People’s Republic of China), Yi Sun (Zhejiang University, Hangzhou, People's Republic of China) for sharing reagents. This work was supported by grants from the National Natural Science Foundation of China, 81470332 and 81272211 to HL, and 81372205 to GQ and New Investigator Foundation, State Education Ministry of China 20120142120097 to HL.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Oncogene website
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