PUBLICATION

Disruption of asxl1 results in myeloproliferative neoplasms in zebrafish

Authors
Gjini, E., Jing, C.B., Nguyen, A.T., Reyon, D., Gans, E., Kesarsing, M., Peterson, J., Pozdnyakova, O., Rodig, S.J., Mansour, M.R., Joung, K., Look, A.T.
ID
ZDB-PUB-190509-2
Date
2019
Source
Disease models & mechanisms   12(5): (Journal)
Registered Authors
Gjini, Evisa, Jing, Chang-Bin, Look, A. Thomas, Mansour, Marc, Nguyen, Ashley
Keywords
Apoptosis, Genome editing, Hematopoietic stem cells, Myeloproliferative neoplasms, Tet2
MeSH Terms
  • Animals
  • Apoptosis
  • Base Sequence
  • Bone Marrow Neoplasms/pathology*
  • Cell Survival
  • Embryo, Nonmammalian/metabolism
  • Gene Editing
  • Hematopoietic Stem Cells/metabolism
  • Leukemia, Myeloid, Acute/pathology
  • Mutation/genetics*
  • Organogenesis
  • Up-Regulation/genetics
  • Zebrafish/embryology
  • Zebrafish/metabolism*
  • Zebrafish Proteins/metabolism*
PubMed
31064769 Full text @ Dis. Model. Mech.
Abstract
Somatic loss-of-function mutations of the additional sex combs-like transcriptional regulator 1 (ASXL1) gene are common genetic abnormalities in human myeloid malignancies and induce clonal expansion of mutated hematopoietic stem cells (HSCs). To understand how ASXL1 disruption leads to myeloid cell transformation, we generated asxl1 haploinsufficient and null zebrafish lines using genome-editing technology. Here, we show that homozygous loss of asxl1 leads to apoptosis of newly formed HSCs. Apoptosis occurred via the mitochondrial apoptotic pathway mediated by upregulation of bim and bid Half of the asxl1+/- zebrafish had myeloproliferative neoplasms (MPNs) by 5 months of age. Heterozygous loss of asxl1 combined with heterozygous loss of tet2 led to a more penetrant MPN phenotype, while heterozygous loss of asxl1 combined with complete loss of tet2 led to acute myeloid leukemia (AML). These findings support the use of asxl1+/- zebrafish as a strategy to identify small-molecule drugs to suppress the growth of asxl1 mutant but not wild-type HSCs in individuals with somatically acquired inactivating mutations of ASXL1.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes