Disruption of asxl1 results in myeloproliferative neoplasms in zebrafish

Somatic loss-of-function mutations of the additional sex combs-like transcriptional regulator 1 ( ) gene are common genetic abnormalities in human myeloid malignancies and induce clonal expansion of mutated hematopoietic stem cells (HSCs). To understand how disruption leads to myeloid cell transform...

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Bibliographic Details
Published in:Disease models & mechanisms 2019-05, Vol.12 (5)
Main Authors: Gjini, Evisa, Jing, Chang-Bin, Nguyen, Ashley T, Reyon, Deepak, Gans, Emma, Kesarsing, Michiel, Peterson, Joshua, Pozdnyakova, Olga, Rodig, Scott J, Mansour, Marc R, Joung, Keith, Look, A Thomas
Format: Article
Language:English
Subjects:
Amino acids
Animals
Apoptosis
Base Sequence
Binding sites
Bone Marrow Neoplasms - pathology
Cell Survival
Embryo, Nonmammalian - metabolism
Embryos
Gene Editing
Gene expression
Genome editing
Genomes
Hematopoietic stem cells
Hematopoietic Stem Cells - metabolism
Leukemia
Leukemia, Myeloid, Acute - pathology
Morphology
Mutation
Mutation - genetics
Myeloproliferative neoplasms
Neoplasia
Organogenesis
Proteins
Repressor Proteins - metabolism
Tet2
Tumors
Up-Regulation - genetics
Zebra
Zebrafish
Zebrafish - embryology
Zebrafish - metabolism
Zebrafish Proteins - metabolism
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Summary:Somatic loss-of-function mutations of the additional sex combs-like transcriptional regulator 1 ( ) gene are common genetic abnormalities in human myeloid malignancies and induce clonal expansion of mutated hematopoietic stem cells (HSCs). To understand how disruption leads to myeloid cell transformation, we generated haploinsufficient and null zebrafish lines using genome-editing technology. Here, we show that homozygous loss of leads to apoptosis of newly formed HSCs. Apoptosis occurred via the mitochondrial apoptotic pathway mediated by upregulation of and Half of the zebrafish had myeloproliferative neoplasms (MPNs) by 5 months of age. Heterozygous loss of combined with heterozygous loss of led to a more penetrant MPN phenotype, while heterozygous loss of combined with complete loss of led to acute myeloid leukemia (AML). These findings support the use of zebrafish as a strategy to identify small-molecule drugs to suppress the growth of mutant but not wild-type HSCs in individuals with somatically acquired inactivating mutations of .
ISSN:1754-8403
1754-8411
1754-8411
DOI:10.1242/dmm.035790