Disruption of 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 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 .