Cancer -associated mutations in XPO1 transform cells through altered nuclear export signal recognition

Proper nucleocytoplasmic distribution of proteins is essential to cellular homeostasis but what role the altered nuclear export machinery commonly described in cancer cells plays in cancer initiation is not known. Here, genomic analysis of 42,793 cancers identified recurrent mutational hotspots in XPO1, the main nuclear export receptor in eukaryotic cells. Expression of XPO1 mutations in vivo was sufficient to initiate clonal, B-lymphoproliferative disorders by altering the constellation of proteins exported from the nucleus based on amino acid charge C-terminal to their nuclear export signal. Impaired export of one such protein, the NFkB inhibitor IB enhanced NFkB signaling, a pathway frequently activated by somatic mutations in cancers enriched in XPO1 mutations. These data identify change-of-function mutations in nuclear export as novel drivers of tumorigenesis. Changes in amino acid charges created by mutations in XPO1 lead to sequence-specific effects on nuclear export signal recognition and promote malignant transformation.

蛋白质的正常核质分布对于细胞稳态至关重要，但癌细胞中常见的核输出机器（nuclear export machinery）异常在癌症发生中发挥何种作用，目前仍不明确。本研究通过对42793例癌症样本的基因组分析，在真核细胞主要的核输出受体XPO1中发现了频发突变热点。在体内表达XPO1突变，即可通过改变基于核输出信号（nuclear export signal）C端氨基酸电荷的核输出蛋白组构成，诱发克隆性B淋巴细胞增殖性疾病。其中一类蛋白即核因子κB（NFκB）抑制剂IκBα的输出受损，会增强NFκB信号通路活性；而该通路在携带XPO1突变的癌症中，常因体细胞突变被激活。本研究数据证实，核输出功能获得性突变是一类全新的肿瘤发生驱动因素。XPO1突变所引发的氨基酸电荷改变，会对核输出信号识别产生序列特异性影响，进而促进恶性转化。