ASXL1 mutation in clonal hematopoiesis

Abstract

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.