Department of Hematology, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China.
Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin, China.
Hematol Oncol. 2021 Apr;39(2):222-230. doi: 10.1002/hon.2831. Epub 2020 Dec 23.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy. Understanding of the molecular pathogenesis may lead to novel therapeutic targets. Rapamycin, the mammalian target of rapamycin (mTOR) inhibitor, showed inhibitory effects on T-ALL cells. In this study, we showed that rapamycin significantly reduced MYCN mRNA and protein in a concentration-dependent manner in T-ALL cells. Selective knockdown of MYCN by small interfering RNA had similar effects to rapamycin to inhibit T-ALL proliferation and colony formation and to induce G1-phase cell-cycle arrest and apoptosis. The inhibitory effects of rapamycin and MYCN depletion were also found in a Molt-4 xenograft model. Rapamycin and MYCN inhibition suppressed both Wnt/β-catenin and mTOR signaling pathways. The results suggest the effects of rapamycin on adult T-ALL is likely mediated by downregulation of MYCN. The findings suggest MYCN a potential target for the treatment of adult T-ALL. Additionally, dual targeting of mTOR and Wnt/β-catenin pathways may represent a novel strategy in the treatment of adult T-ALL.
T 细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性恶性肿瘤。对其分子发病机制的理解可能会带来新的治疗靶点。雷帕霉素是哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂，对 T-ALL 细胞有抑制作用。在本研究中，我们发现雷帕霉素可浓度依赖性地显著降低 T-ALL 细胞中 MYCN mRNA 和蛋白的表达。通过小干扰 RNA 选择性敲低 MYCN 具有与雷帕霉素相似的抑制 T-ALL 增殖和集落形成、诱导 G1 期细胞周期阻滞和凋亡的作用。在 Molt-4 异种移植模型中也发现了雷帕霉素和 MYCN 耗竭的抑制作用。雷帕霉素和 MYCN 抑制作用抑制了 Wnt/β-catenin 和 mTOR 信号通路。这些结果表明，雷帕霉素对成人 T-ALL 的作用可能是通过下调 MYCN 介导的。这些发现表明 MYCN 是治疗成人 T-ALL 的一个潜在靶点。此外，mTOR 和 Wnt/β-catenin 通路的双重靶向可能代表治疗成人 T-ALL 的一种新策略。
