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.
The EVI1 gene is a transcriptional regulator of hematopoietic stem cell self renewal and its overexpression is associated with adverse prognosis in de novo AML. Whether the overexpression of EVI1 also predicts poor outcome of AML patients undergoing myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first CR (CR1) is still unclear. Thirty-two (21.2%) out of 151 patients were categorized as high EVI1 expression (EVI1+), and 119 (78.8%) patients were categorized as low EVI1 expression (EVI1-). The frequency of EVI1+ was much higher in the adverse-risk group than the intermediate-risk group (53% vs 19%, P=0.005). EVI1+ patients were significantly likely to harbor with translocations involving the MLL gene on 11q23 (8/9). Significantly poor results were observed in the EVI1+ cohort in terms of leukemia-free survival (LFS) (in 24 months 52.6 vs 71.0%, P=0.027), overall survival (OS) (in 24 months 52.8 vs 72.4%, P=0.012), and cumulative incidence of relapse (in 24 months 39.5 vs 22.5%, P=0.013). Multivariable analysis revealed that low EVI1 expression as an independent prognostic factor favoring LFS (hazards ratio=0.47, 95% confidence interval 0.26-0.86, P=0.01) but not OS. Our results indicate high EVI1 expression might predict high risk of relapse in AML patients undergoing myeloablative allo-HSCT in CR1.
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