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Erschienen in: International Journal of Hematology 2/2019

05.12.2018 | Progress in Hematology

Aberrant histone modifications induced by mutant ASXL1 in myeloid neoplasms

verfasst von: Shuhei Asada, Toshio Kitamura

Erschienen in: International Journal of Hematology | Ausgabe 2/2019

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Abstract

An epigenetic modulator Additional sex combs-like 1 (ASXL1) is recurrently mutated in myeloid neoplasms such as myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs). ASXL1 mutations are also frequently detected in clonal hematopoiesis with indeterminate potential (CHIP), which is the clonal expansion of premalignant hematopoietic cells without any evidence of hematological malignancies. Thus, understanding the roles of ASXL1 in hematopoiesis and myeloid neoplasms is a clinically crucial issue. ASXL1 mutations in hematological neoplasms are typically frameshift or nonsense mutations and occur near the 5′ end of the last exon, thereby the transcripts would escape from nonsense-mediated decay, Indeed, we identified the C-terminally truncated mutant protein of ASXL1 in several cell lines derived from patients with myeloid leukemia. In mouse models, expression of the mutant ASXL1 results in impaired hematopoiesis and promotes development of myeloid neoplasms. In addition, recent findings from biochemical analysis have demonstrated that the mutant ASXL1 protein gains new functions including enhancing catalytic activity of BRCA1-associated protein 1 (BAP1), resulting in reduction of H2AK119ub and aberrant gene expression essential for myeloid transformation. In this review, we will focus on the pivotal roles of the mutant ASXL1 on histone modifications and myeloid transformation.
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Metadaten
Titel
Aberrant histone modifications induced by mutant ASXL1 in myeloid neoplasms
verfasst von
Shuhei Asada
Toshio Kitamura
Publikationsdatum
05.12.2018
Verlag
Springer Japan
Erschienen in
International Journal of Hematology / Ausgabe 2/2019
Print ISSN: 0925-5710
Elektronische ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-018-2563-7

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