Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan.
Laboratory of Biomedical Innovation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Elife. 2019 Nov 22;8:e46667. doi: 10.7554/eLife.46667.
We previously demonstrated that CRM1, a major nuclear export factor, accumulates at cluster regions to recruit nucleoporin-fusion protein Nup98HoxA9, resulting in robust activation of genes (Oka et al., 2016). However, whether this phenomenon is general to other leukemogenic proteins remains unknown. Here, we show that two other leukemogenic proteins, nucleoporin-fusion SET-Nup214 and the NPM1 mutant, NPM1c, which contains a nuclear export signal (NES) at its C-terminus and is one of the most frequent mutations in acute myeloid leukemia, are recruited to the cluster region via chromatin-bound CRM1, leading to gene activation in human leukemia cells. Furthermore, we demonstrate that this mechanism is highly sensitive to a CRM1 inhibitor in leukemia cell line. Together, these findings indicate that CRM1 acts as a key molecule that connects leukemogenic proteins to aberrant gene regulation either via nucleoporin-CRM1 interaction (for SET-Nup214) or NES-CRM1 interaction (for NPM1c).
我们之前的研究表明，CRM1 是一种主要的核输出因子，它在 簇区积累以招募核孔蛋白融合蛋白 Nup98HoxA9，从而导致 基因的强烈激活（Oka 等人，2016 年）。然而，这种现象是否普遍适用于其他白血病相关蛋白尚不清楚。在这里，我们发现另外两种白血病相关蛋白，核孔蛋白融合蛋白 SET-Nup214 和 NPM1 突变体 NPM1c，后者的 C 端含有核输出信号（NES），是急性髓系白血病中最常见的突变之一，通过染色质结合的 CRM1 被募集到 簇区，导致人类白血病细胞中 基因的激活。此外，我们证明这种机制对白血病细胞系中的 CRM1 抑制剂高度敏感。总之，这些发现表明 CRM1 作为一个关键分子，通过核孔蛋白-CRM1 相互作用（对于 SET-Nup214）或 NES-CRM1 相互作用（对于 NPM1c），将白血病相关蛋白与异常的 基因调控联系起来。
