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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2017

Open Access 01-12-2017 | Research

The distinct biological implications of Asxl1 mutation and its roles in leukemogenesis revealed by a knock-in mouse model

Authors: Yueh-Chwen Hsu, Yu-Chiao Chiu, Chien-Chin Lin, Yuan-Yeh Kuo, Hsin-An Hou, Yi-Shiuan Tzeng, Chein-Jun Kao, Po-Han Chuang, Mei-Hsuan Tseng, Tzu-Hung Hsiao, Wen-Chien Chou, Hwei-Fang Tien

Published in: Journal of Hematology & Oncology | Issue 1/2017

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Abstract

Background

Additional sex combs-like 1 (ASXL1) is frequently mutated in myeloid malignancies. Recent studies showed that hematopoietic-specific deletion of Asxl1 or overexpression of mutant ASXL1 resulted in myelodysplasia-like disease in mice. However, actual effects of a “physiological” dose of mutant ASXL1 remain unexplored.

Methods

We established a knock-in mouse model bearing the most frequent Asxl1 mutation and studied its pathophysiological effects on mouse hematopoietic system.

Results

Heterozygotes (Asxl1 tm/+ ) marrow cells had higher in vitro proliferation capacities as shown by more colonies in cobblestone-area forming assays and by serial re-plating assays. On the other hand, donor hematopoietic cells from Asxl1 tm/+ mice declined faster in recipients during transplantation assays, suggesting compromised long-term in vivo repopulation abilities. There were no obvious blood diseases in mutant mice throughout their life-span, indicating Asxl1 mutation alone was not sufficient for leukemogenesis. However, this mutation facilitated engraftment of bone marrow cell overexpressing MN1. Analyses of global gene expression profiles of ASXL1-mutated versus wild-type human leukemia cells as well as heterozygote versus wild-type mouse marrow precursor cells, with or without MN1 overexpression, highlighted the association of in vivo Asxl1 mutation to the expression of hypoxia, multipotent progenitors, hematopoietic stem cells, KRAS, and MEK gene sets. ChIP-Seq analysis revealed global patterns of Asxl1 mutation-modulated H3K27 tri-methylation in hematopoietic precursors.

Conclusions

We proposed the first Asxl1 mutation knock-in mouse model and showed mutated Asxl1 lowered the threshold of MN1-driven engraftment and exhibited distinct biological functions on physiological and malignant hematopoiesis, although it was insufficient to lead to blood malignancies.
Appendix
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Metadata
Title
The distinct biological implications of Asxl1 mutation and its roles in leukemogenesis revealed by a knock-in mouse model
Authors
Yueh-Chwen Hsu
Yu-Chiao Chiu
Chien-Chin Lin
Yuan-Yeh Kuo
Hsin-An Hou
Yi-Shiuan Tzeng
Chein-Jun Kao
Po-Han Chuang
Mei-Hsuan Tseng
Tzu-Hung Hsiao
Wen-Chien Chou
Hwei-Fang Tien
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2017
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-017-0508-x

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