Division of Cellular Therapy, The Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Division of Cellular Therapy, The Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Exp Hematol. 2020 Mar;83:74-84. doi: 10.1016/j.exphem.2020.01.002. Epub 2020 Jan 13.
Recent advances in DNA sequencing technologies have enhanced our knowledge about several diseases. Coupled with easy accessibility to blood samples, hematology plays a leading role in understanding the process of carcinogenesis. Clonal hematopoiesis (CH) with somatic mutations is observed in at least 10% of people over 65 years of age, without apparent hematologic disorders. CH is associated with increased risk of hematologic malignancies, which is indicative of a pre-malignant condition. Therefore, a better understanding of CH will help elucidate the mechanism of multi-step tumorigenesis in the hematopoietic system. Somatic mutations of ASXL1 are frequently detected in CH and myeloid malignancies. Although ASXL1 does not have any catalytic activity, it is involved in multiple histone modifications including H3K4me3, H3K27me3, and H2AK119Ub, suggesting its function as a scaffolding protein. Most ASXL1 mutations detected in CH and myeloid malignancies are frameshift or nonsense mutations of the last exon, generating a C-terminally truncated protein. Deletion of Asxl1 or expression of mutant ASXL1 in mice alters histone modifications and facilitates aberrant gene expression, resulting in myeloid transformation. On the contrary, these mice exhibit impaired functioning of hematopoietic stem cells (HSCs), suggesting the negative effects of ASXL1 mutations on stem cell function. Thus, how ASXL1 mutations induce a clonal advantage of hematopoietic cells and subsequent CH development has not been elucidated. Here, we have reviewed the current literature that enhances our understanding of ASXL1, including its mutational landscape, function, and involvement of its mutation in pathogenesis of CH and myeloid malignancies. Finally, we discuss the potential causes of CH harboring ASXL1 mutations with our latest knowledge.
近年来，DNA 测序技术的进步提高了我们对多种疾病的认识。由于血液样本易于获取，血液学在理解致癌过程中发挥着主导作用。克隆性造血（CH）伴有体细胞突变，在至少 10%的 65 岁以上人群中观察到，没有明显的血液系统疾病。CH 与血液恶性肿瘤风险增加相关，表明其处于恶性前状态。因此，更好地了解 CH 将有助于阐明造血系统多步肿瘤发生的机制。ASXL1 的体细胞突变在 CH 和髓系恶性肿瘤中经常被检测到。尽管 ASXL1 没有任何催化活性，但它参与包括 H3K4me3、H3K27me3 和 H2AK119Ub 在内的多种组蛋白修饰，表明其作为支架蛋白的功能。在 CH 和髓系恶性肿瘤中检测到的大多数 ASXL1 突变是最后一个外显子的移码或无义突变，产生 C 端截断的蛋白。在小鼠中删除 Asxl1 或表达突变型 ASXL1 会改变组蛋白修饰并促进异常基因表达，导致髓系转化。相反，这些小鼠表现出造血干细胞（HSCs）功能受损，表明 ASXL1 突变对干细胞功能的负面影响。因此，ASXL1 突变如何导致造血细胞的克隆优势和随后的 CH 发展尚未阐明。在这里，我们回顾了增强我们对 ASXL1 理解的当前文献，包括其突变景观、功能及其突变在 CH 和髓系恶性肿瘤发病机制中的作用。最后，我们根据我们的最新知识讨论了携带 ASXL1 突变的 CH 的潜在原因。
