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Disruption of asxl1 results in myeloproliferative neoplasms in zebrafish

Gjini, E; Jing, C-B; Nguyen, AT; Reyon, D; Gans, E; Kesarsing, M; Peterson, J; ... Look, AT; + view all (2019) Disruption of asxl1 results in myeloproliferative neoplasms in zebrafish. Disease Models & Mechanisms , 12 (5) , Article dmm035790. 10.1242/dmm.035790. Green open access

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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.

Type: Article
Title: Disruption of asxl1 results in myeloproliferative neoplasms in zebrafish
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1242/dmm.035790
Publisher version: https://doi.org/10.1242/dmm.035790
Language: English
Additional information: Copyright © 2019. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Keywords: Apoptosis, Genome editing, Hematopoietic stem cells, Myeloproliferative neoplasms, Tet2
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: http://discovery.ucl.ac.uk/id/eprint/10074996
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