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
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
Figures
Figure Gallery
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Errata and Notes