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Hypomorphic mTOR downregulates CDK6 and delays thymic Pre-T LBL tumorigenesis
Molecular Cancer Therapeutics ( IF 5.7 ) Pub Date : 2020-08-03 , DOI: 10.1158/1535-7163.mct-19-0671
Joy M Gary 1, 2 , John K Simmons 1 , Jinfei Xu 3 , Shuling Zhang 1 , Tyler J Peat 1 , Nicholas Watson 1 , Benjamin J Gamache 1, 4 , Ke Zhang 1 , Alexander L Kovalchuk 5 , Aleksandra M Michalowski 1 , Jin-Qiu Chen 1 , Tuddow Thaiwong 2 , Matti Kiupel 2 , Snehal Gaikwad 1 , Maudeline Etienne 1 , R Mark Simpson 1 , Wendy Dubois 1 , Joseph R Testa 3 , Beverly A Mock 1
Affiliation  

PI3K/AKT/mTOR pathway hyperactivation is frequent in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL). To model inhibition of mTOR, pre–T-cell lymphoblastic leukemia/lymphoma (pre-T LBL) tumor development was monitored in mice with T lymphocyte–specific, constitutively active AKT (Lck-MyrAkt2) that were either crossed to mTOR knockdown (KD) mice or treated with the mTOR inhibitor everolimus. Lck-MyrAkt2;mTOR KD mice lived significantly longer than Lck-MyrAkt2;mTOR wild-type (WT) mice, although both groups ultimately developed thymic pre-T LBL. An increase in survival was also observed when Lck-MyrAkt2;mTOR WT mice were treated for 8 weeks with everolimus. The transcriptional profiles of WT and KD thymic lymphomas were compared, and Ingenuity Pathway Upstream Regulator Analysis of differentially expressed genes in tumors from mTOR WT versus KD mice identified let-7 and miR-21 as potential regulatory genes. mTOR KD mice had higher levels of let-7a and miR-21 than mTOR WT mice, and rapamycin induced their expression in mTOR WT cells. CDK6 was one of the most downregulated targets of both let-7 and miR21 in mTOR KD tumors. CDK6 overexpression and decreased expression of let-7 in mTOR KD cells rescued a G1 arrest phenotype. Combined mTOR (rapamycin) and CDK4/6 (palbociclib) inhibition decreased tumor size and proliferation in tumor flank transplants, increased survival in an intravenous transplant model of disseminated leukemia compared with single agent treatment, and cooperatively decreased cell viability in human T-ALL/LBL cell lines. Thus, mTOR KD mice provide a model to explore drug combinations synergizing with mTOR inhibitors and can be used to identify downstream targets of inhibition.

中文翻译:

亚型 mTOR 下调 CDK6 并延迟胸腺 Pre-T LBL 肿瘤发生

PI3K/AKT/mTOR 通路过度激活在 T 细胞急性淋巴细胞白血病/淋巴瘤 (T-ALL/LBL) 中很常见。为了模拟 mTOR 的抑制作用,在具有 T 淋巴细胞特异性、组成型活性 AKT (Lck-MyrAkt2) 的小鼠中监测前 T 细胞淋巴细胞白血病/淋巴瘤 (pre-T LBL) 肿瘤的发展,这些 AKT 与 mTOR 敲低 (KD ) 小鼠或用 mTOR 抑制剂依维莫司治疗。Lck-MyrAkt2;mTOR KD 小鼠的寿命明显长于 Lck-MyrAkt2;mTOR 野生型 (WT) 小鼠,尽管两组最终都出现了胸腺前 T LBL。当 Lck-MyrAkt2;mTOR WT 小鼠用依维莫司治疗 8 周时,也观察到存活率增加。比较了 WT 和 KD 胸腺淋巴瘤的转录谱,和 Ingenuity Pathway Upstream Regulator 对 mTOR WT 与 KD 小鼠肿瘤中差异表达基因的分析将 let-7 和 miR-21 确定为潜在的调节基因。mTOR KD 小鼠的 let-7a 和 miR-21 水平高于 mTOR WT 小鼠,并且雷帕霉素诱导了它们在 mTOR WT 细胞中的表达。CDK6 是 mTOR KD 肿瘤中 let-7 和 miR21 最下调的靶标之一。mTOR KD 细胞中 CDK6 过表达和 let-7 表达降低挽救了 G1 期阻滞表型。与单药治疗相比,mTOR(雷帕霉素)和 CDK4/6(palbociclib)联合抑制降低了肿瘤侧腹移植的肿瘤大小和增殖,增加了播散性白血病静脉移植模型的存活率,并协同降低了人类 T-ALL/ 中的细胞活力LBL 细胞系。因此,
更新日期:2020-08-03
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