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The role of ASXL1 in hematopoiesis and myeloid malignancies

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Recent high-throughput genome-wide sequencing studies have identified recurrent somatic mutations in myeloid neoplasms. An epigenetic regulator, Additional sex combs-like 1 (ASXL1), is one of the most frequently mutated genes in… Click to show full abstract

Recent high-throughput genome-wide sequencing studies have identified recurrent somatic mutations in myeloid neoplasms. An epigenetic regulator, Additional sex combs-like 1 (ASXL1), is one of the most frequently mutated genes in all subtypes of myeloid malignancies. ASXL1 mutations are also frequently detected in clonal hematopoiesis, which is associated with an increased risk of mortality. Therefore, it is important to understand how ASXL1 mutations contribute to clonal expansion and myeloid transformation in hematopoietic cells. Studies using ASXL1-depleted human hematopoietic cells and Asxl1 knockout mice have shown that deletion of wild-type ASXL1 protein leads to impaired hematopoiesis and accelerates myeloid malignancies via loss of interaction with polycomb repressive complex 2 proteins. On the other hand, ASXL1 mutations in myeloid neoplasms typically occur near the last exon and result in the expression of C-terminally truncated mutant ASXL1 protein. Biological studies and biochemical analyses of this variant have shed light on its dominant-negative and gain-of-function features in myeloid transformation via a variety of epigenetic changes. Based on these results, it would be possible to establish novel promising therapeutic strategies for myeloid malignancies harboring ASXL1 mutations by blocking interactions between ASXL1 and associating epigenetic regulators. Here, we summarize the clinical implications of ASXL1 mutations, the role of wild-type ASXL1 in normal hematopoiesis, and oncogenic functions of mutant ASXL1 in myeloid neoplasms.

Keywords: role; myeloid malignancies; asxl1 mutations; hematopoiesis

Journal Title: Cellular and Molecular Life Sciences
Year Published: 2019

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