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Aberrant histone modifications induced by mutant ASXL1 in myeloid neoplasms

  • Shuhei Asada
  • Toshio Kitamura
Progress in Hematology Epigenetic abnormalities and therapies for hematological malignancies

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.

Keywords

ASXL1 Histone modifications H2AK119ub BAP1 Myeloid neoplasms 

Notes

Acknowledgements

This work was supported by a Grant-in-Aid Scientific Research B from the Ministry of Education, Culture, Sports, Science and Technology of Japan (15H04855, TK), a grant from the Tokyo Biochemical Research Foundation (TK), a grant from the Uehara Memorial Foundation (TK).

Compliance with ethical standards

Conflict of interest

The authors have declared that no conflict of interest exists.

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Copyright information

© The Japanese Society of Hematology 2018

Authors and Affiliations

  1. 1.Division of Cellular Therapy, Advanced Clinical Research Center, Division of Stem Cell Signaling, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical ScienceThe University of TokyoTokyoJapan

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