PUBLICATION
Asxl1 C-terminal mutation perturbs neutrophil differentiation in zebrafish
- Authors
- Fang, X., Xu, S., Zhang, Y., Xu, J., Huang, Z., Liu, W., Wang, S., Yen, K., Zhang, W.
- ID
- ZDB-PUB-210124-2
- Date
- 2021
- Source
- Leukemia 35(8): 2299-2310 (Journal)
- Registered Authors
- Zhang, Wenqing
- Keywords
- none
- Datasets
- GEO:GSE142214
- MeSH Terms
-
- Animals
- Cell Differentiation
- Embryo, Nonmammalian/metabolism
- Embryo, Nonmammalian/pathology*
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology*
- Leukemia, Myelomonocytic, Chronic/genetics
- Leukemia, Myelomonocytic, Chronic/metabolism
- Leukemia, Myelomonocytic, Chronic/pathology*
- Mutation*
- Neutrophils/metabolism
- Neutrophils/pathology*
- Phenotype
- Repressor Proteins/genetics
- Repressor Proteins/metabolism*
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 33483612 Full text @ Leukemia
Citation
Fang, X., Xu, S., Zhang, Y., Xu, J., Huang, Z., Liu, W., Wang, S., Yen, K., Zhang, W. (2021) Asxl1 C-terminal mutation perturbs neutrophil differentiation in zebrafish. Leukemia. 35(8):2299-2310.
Abstract
ASXL1 is one of the most frequently mutated genes in malignant myeloid diseases. In patients with myeloid malignancies, ASXL1 mutations are usually heterozygous frameshift or nonsense mutations leading to C-terminal truncation. Current disease models have predominantly total loss of ASXL1 or overexpressed C-terminal truncations. These models cannot fully recapitulate leukemogenesis and disease progression. We generated an endogenous C-terminal-truncated Asxl1 mutant in zebrafish that mimics human myeloid malignancies. At the embryonic stage, neutrophil differentiation was explicitly blocked. At 6 months, mutants initially exhibited a myelodysplastic syndrome-like phenotype with neutrophilic dysplasia. At 1 year, about 13% of mutants further acquired the phenotype of monocytosis, which mimics chronic myelomonocytic leukemia, or increased progenitors, which mimics acute myeloid leukemia. These features are comparable to myeloid malignancy progression in humans. Furthermore, transcriptome analysis, inhibitor treatment, and rescue assays indicated that asxl1-induced neutrophilic dysplasia was associated with reduced expression of bmi1a, a subunit of polycomb repressive complex 1 and a reported myeloid leukemia-associated gene. Our model demonstrated that neutrophilic dysplasia caused by asxl1 mutation is a foundation for the progression of myeloid malignancies, and illustrated a possible effect of the Asxl1-Bmi1a axis on regulating neutrophil development.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping