DEPTOR is a direct NOTCH1 target that promotes cell proliferation and survival in T-cell leukemia
DEPTOR is a direct NOTCH1 target that promotes cell proliferation and survival in T-cell leukemia
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DEPTOR 是 NOTCH1 的直接靶标，可促进 T 细胞白血病的细胞增殖和存活
DOI：
10.1038/onc.2016.275
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发表时间：
2017-02-23
期刊：
影响因子：
8
通讯作者：
Qing, G.
中科院分区：
文献类型：
--
作者：
Hu, Y.;Su, H.;Qing, G.
NOTCH 1信号通路的异常激活在T细胞急性淋巴细胞白血病（T-ALL）的发病机制中起着至关重要的作用。然而，NOTCH 1下游驱动T细胞白血病发生的分子事件仍不完全清楚。从全基因组基因表达谱开始寻找重要的NOTCH 1转录靶点，我们鉴定了含DEP结构域的mTOR相互作用蛋白（DEPTOR），该蛋白以前在多发性骨髓瘤中显示出重要性，但在其他血液恶性肿瘤中的功能尚不清楚。从机制上讲，我们证明了NOTCH 1直接结合并激活T-ALL细胞中的人DEPTOR启动子。DEPTOR耗竭抑制细胞增殖，减弱糖酵解代谢，增强细胞死亡，而异位表达的DEPTOR显着促进细胞生长和糖酵解。我们进一步表明，在T-ALL细胞中，DEPTOR耗竭抑制而其过表达增强AKT活化。重要的是，AKT抑制完全消除了DEPTOR介导的细胞生长优势。此外，在人T-ALL异种移植模型中，DEPTOR耗竭显著延迟了T-ALL的发作，并导致白血病母细胞中AKT活化的显著降低。因此，我们揭示了一种新的机制参与NOTCH 1驱动的白血病，确定转录控制的DEPTOR和AKT的调节作为额外的关键要素的白血病程序激活的NOTCH 1。
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.