The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Essential for Malignant Conversion in MYC-Driven Lymphoma.

IF 11.5 Q1 HEMATOLOGY
Shima Nakanishi, Jiannong Li, Anders E Berglund, Youngchul Kim, Yonghong Zhang, Ling Zhang, Chunying Yang, Jinming Song, Raghavendra G Mirmira, John L Cleveland
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引用次数: 1

Abstract

The MYC oncoprotein is activated in a broad spectrum of human malignancies and transcriptionally reprograms the genome to drive cancer cell growth. Given this, it is unclear if targeting a single effector of MYC will have therapeutic benefit. MYC activates the polyamine-hypusine circuit, which posttranslationally modifies the eukaryotic translation factor eIF5A. The roles of this circuit in cancer are unclear. Here we report essential intrinsic roles for hypusinated eIF5A in the development and maintenance of MYC-driven lymphoma, where the loss of eIF5A hypusination abolishes malignant transformation of MYC-overexpressing B cells. Mechanistically, integrating RNA sequencing, ribosome sequencing, and proteomic analyses revealed that efficient translation of select targets is dependent upon eIF5A hypusination, including regulators of G1-S phase cell-cycle progression and DNA replication. This circuit thus controls MYC's proliferative response, and it is also activated across multiple malignancies. These findings suggest the hypusine circuit as a therapeutic target for several human tumor types.

Significance: Elevated EIF5A and the polyamine-hypusine circuit are manifest in many malignancies, including MYC-driven tumors, and eIF5A hypusination is necessary for MYC proliferative signaling. Not-ably, this circuit controls an oncogenic translational program essential for the development and maintenance of MYC-driven lymphoma, supporting this axis as a target for cancer prevention and treatment. See related commentary by Wilson and Klein, p. 248. This article is highlighted in the In This Issue feature, p. 247.

多胺-秋水仙碱回路控制着对 MYC 驱动的淋巴瘤恶性转化至关重要的致癌转化程序。
MYC 癌症蛋白在多种人类恶性肿瘤中被激活,并通过转录重编程基因组来驱动癌细胞生长。有鉴于此,目前还不清楚针对 MYC 的单一效应物是否会产生治疗效果。MYC 可激活多胺-羽扇豆碱回路,该回路可对真核翻译因子 eIF5A 进行翻译后修饰。该回路在癌症中的作用尚不清楚。在这里,我们报告了eIF5A低复性在MYC驱动的淋巴瘤的发展和维持过程中的重要内在作用,其中eIF5A低复性的缺失会取消MYC过表达B细胞的恶性转化。从机理上讲,通过整合 RNA 测序、核糖体测序和蛋白质组分析发现,选择靶点的高效翻译依赖于 eIF5A 的低浓化,包括 G1-S 期细胞周期进展和 DNA 复制的调节因子。因此,这一回路控制着 MYC 的增殖反应,它也在多种恶性肿瘤中被激活。这些研究结果表明,次碱基回路是几种人类肿瘤类型的治疗靶点:意义:EIF5A和多胺-肌松蛋白回路的升高在许多恶性肿瘤中都有表现,包括MYC驱动的肿瘤。值得注意的是,该回路控制着对 MYC 驱动的淋巴瘤的发展和维持至关重要的致癌转化程序,支持将该轴作为癌症预防和治疗的靶点。参见 Wilson 和 Klein 的相关评论,第 248 页。第 247 页的 "本期特写 "重点介绍了这篇文章。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
12.70
自引率
1.80%
发文量
139
期刊介绍: The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes. The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence. Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.
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