RHEB is a potential therapeutic target in T cell acute lymphoblastic leukemia
RHEB is a potential therapeutic target in T cell acute lymphoblastic leukemia
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DOI：
10.1016/j.bbrc.2022.06.089
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发表时间：
2022-07-08
影响因子：
3.1
通讯作者：
Hirao, Atsushi
中科院分区：
文献类型：
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作者：
Pham, Loc Thi;Peng, Hui;Hirao, Atsushi
T细胞急性淋巴细胞白血病(T-ALL)是一种未成熟T淋巴细胞的侵袭性恶性肿瘤。虽然已经开发了各种治疗方法，但化疗的难治性和复发导致该病预后不佳，需要进一步的治疗策略。在此，我们报告了富含于脑中的RAS同系物(Rheb)，它是mTOR Complex 1活性的关键调节因子，是T-ALL治疗的潜在靶点。在这项研究中，我们建立了一个全面靶向mTOR上下游途径的sgRNA文库，包括自噬。CRISPR/Cas9基因缺失筛查揭示了mTOR相关分子在T-ALL细胞存活中的关键作用。在这些调节剂中，我们专注于Rheb，因为我们之前发现它对小鼠的正常造血是必不可少的。转录组和代谢分析显示，Rheb缺乏抑制了从头核苷酸的生物合成，导致人类T-ALL细胞死亡。重要的是，Rheb缺乏抑制了小鼠和异种移植模型中的肿瘤生长。我们的数据为通过Rheb特异性抑制有效治疗T-ALL提供了一种潜在的策略。(C)2022 Elsevier Inc.保留所有权利。
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of immature T lymphocytes. Although various therapeutic approaches have been developed, refractoriness of chemotherapy and relapse cause a poor prognosis of the disease and further therapeutic strategies are required. Here, we report that Ras homolog enriched in brain (RHEB), a critical regulator of mTOR complex 1 activity, is a potential target for T-ALL therapy. In this study, we established an sgRNA library that comprehensively targeted mTOR upstream and downstream pathways, including autophagy. CRISPR/Cas9 dropout screening revealed critical roles of mTOR-related molecules in T-ALL cell survival. Among the regulators, we focused on RHEB because we previously found that it is dispensable for normal hematopoiesis in mice. Transcriptome and metabolic analyses revealed that RHEB deficiency suppressed de novo nucleotide biosynthesis, leading to human T-ALL cell death. Importantly, RHEB deficiency suppressed tumor growth in both mouse and xenograft models. Our data provide a potential strategy for efficient therapy of T-ALL by RHEB-specific inhibition. (C) 2022 Elsevier Inc. All rights reserved.