1. The distinct biological implications of Asxl1 mutation and its roles in leukemogenesis revealed by a knock-in mouse model
- Author
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Chein-Jun Kao, Yu-Chiao Chiu, Wen-Chien Chou, Mei-Hsuan Tseng, Hwei-Fang Tien, Chien-Chin Lin, Yuan-Yeh Kuo, Po-Han Chuang, Yueh-Chwen Hsu, Tzu-Hung Hsiao, Yi-Shiuan Tzeng, and Hsin-An Hou
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Myeloid ,Mutant ,medicine.disease_cause ,Hematopoietic stem cell ,Mice ,Gene Knock-In Techniques ,Oncogene Proteins ,Mutation ,Hematology ,Leukemia ,MN1 ,lcsh:Diseases of the blood and blood-forming organs ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Gene Expression Regulation, Neoplastic ,Haematopoiesis ,medicine.anatomical_structure ,Oncology ,Stem cell ,medicine.medical_specialty ,Bone Marrow Cells ,Biology ,lcsh:RC254-282 ,03 medical and health sciences ,Internal medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Progenitor cell ,Molecular Biology ,Cell Proliferation ,lcsh:RC633-647.5 ,Research ,Tumor Suppressor Proteins ,Engraftment ,Hematopoietic Stem Cells ,Hematopoiesis ,Mice, Inbred C57BL ,Repressor Proteins ,Disease Models, Animal ,030104 developmental biology ,Myelodysplastic Syndromes ,Cancer research ,Trans-Activators ,Asxl1 - 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. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0508-x) contains supplementary material, which is available to authorized users.
- Published
- 2017