XPO1 in B cell hematological malignancies: from recurrent somatic mutations to targeted therapy.
XPO1 in B cell hematological malignancies: from recurrent somatic mutations to targeted therapy.
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DOI：
10.1186/s13045-017-0412-4
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发表时间：
2017-02-14
影响因子：
28.5
通讯作者：
Jardin F
中科院分区：
文献类型：
--
作者：
Camus V;Miloudi H;Taly A;Sola B;Jardin F
最近的许多出版物强调了关键的真核核输出蛋白 Exportin-1 (XPO1) 在几种恶性肿瘤的肿瘤发生中的重要作用，并且有新的证据表明 XPO1 抑制是抗癌的关键靶标。最近，随着核输出化合物选择性抑制剂的开发，XPO1 的药理学抑制作用得到了临床验证，在患有大量预先治疗的血液恶性肿瘤的患者中显示出有趣的抗肿瘤活性。最近的报告显示，编码 XPO1 的基因发生分子改变，并在以下两种具有相似表型和自然史的血液恶性肿瘤中显示出突变热点（E571K）：原发性纵隔弥漫性大 B 细胞淋巴瘤和经典霍奇金淋巴瘤。新出现的证据表明突变体 XPO1 E571K 在致癌过程中发挥作用，并且可以使用高度灵敏的分子生物学技术（例如数字 PCR 和新一代测序）在患者的肿瘤和浆细胞游离 DNA 中对这种变异进行定量。因此，有人提出 XPO1 E571K 变体可以作为这种情况下的微小残留病工具。为了澄清和总结有关 XPO1 在 B 细胞血液恶性肿瘤中作用的最新发现，我们进行了文献检索，介绍了确定 XPO1 分子改变的概况、它们对 XPO1 蛋白的影响、它们作为生物标志物的兴趣以及对 B 细胞血液恶性肿瘤中新的 XPO1 靶向疗法的开发的主要出版物。
Many recent publications highlight the large role of the pivotal eukaryotic nuclear export protein exportin-1 (XPO1) in the oncogenesis of several malignancies, and there is emerging evidence that XPO1 inhibition is a key target against cancer. The clinical validation of the pharmacological inhibition of XPO1 was recently achieved with the development of the selective inhibitor of nuclear export compounds, displaying an interesting anti-tumor activity in patients with massive pre-treated hematological malignancies. Recent reports have shown molecular alterations in the gene encoding XPO1 and showed a mutation hotspot (E571K) in the following two hematological malignancies with similar phenotypes and natural histories: primary mediastinal diffuse large B cell lymphoma and classical Hodgkin’s lymphoma. Emerging evidence suggests that the mutant XPO1 E571K plays a role in carcinogenesis, and this variant is quantifiable in tumor and plasma cell-free DNA of patients using highly sensitive molecular biology techniques, such as digital PCR and next-generation sequencing. Therefore, it was proposed that the XPO1 E571K variant may serve as a minimal residual disease tool in this setting. To clarify and summarize the recent findings on the role of XPO1 in B cell hematological malignancies, we conducted a literature search to present the major publications establishing the landscape of XPO1 molecular alterations, their impact on the XPO1 protein, their interest as biomarkers, and investigations into the development of new XPO1-targeted therapies in B cell hematological malignancies.