JAK2V617F homozygosity drives a phenotypic switch in myeloproliferative neoplasms, but is insufficient to sustain disease

Li, J, Kent, DG, Godfrey, AL, Manning, H, Nangalia, J, Aziz, A ORCID: https://orcid.org/0000-0002-8774-0348, Chen, E, Saeb-Parsy, K, Fink, J, Sneade, R, Hamilton, TL, Pask, DC, Silber, Y, Zhao, X, Ghevaert, C, Liu, P and Green, AR 2014, 'JAK2V617F homozygosity drives a phenotypic switch in myeloproliferative neoplasms, but is insufficient to sustain disease' , Blood, 123 (20) , pp. 3139-3151.

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Genomic regions of acquired uniparental disomy (UPD) are common in malignancy and frequently harbor mutated oncogenes. Homozygosity for such gain-of-function mutations is thought to modulate tumor phenotype, but direct evidence has been elusive. Polycythemia vera (PV) and essential thrombocythemia (ET), 2 subtypes of myeloproliferative neoplasms, are associated with an identical acquired JAK2V617F mutation but the mechanisms responsible for distinct clinical phenotypes remain unclear. We provide direct genetic evidence and demonstrate that homozygosity for human JAK2V617F in knock-in mice results in a striking phenotypic switch from an ET-like to PV-like phenotype. The resultant erythrocytosis is driven by increased numbers of early erythroid progenitors and enhanced erythroblast proliferation, whereas reduced platelet numbers are associated with impaired platelet survival. JAK2V617F-homozygous mice developed a severe hematopoietic stem cell defect, suggesting that additional lesions are needed to sustain clonal expansion. Together, our results indicate that UPD for 9p plays a causal role in the PV phenotype in patients as a consequence of JAK2V617F homozygosity. The generation of a JAK2V617F allelic series of mice with a dose-dependent effect on hematopoiesis provides a powerful model for studying the consequences of mutant JAK2 homozygosity.

Item Type: Article
Themes: Health and Wellbeing
Schools: Schools > School of Environment and Life Sciences > Biomedical Research Centre
Journal or Publication Title: Blood
Publisher: American Society of Hematology
Refereed: Yes
ISSN: 0006-4971
Funders: CRUK, LLR
Depositing User: Dr Athar Aziz
Date Deposited: 30 Jan 2015 17:57
Last Modified: 15 Feb 2022 19:02
URI: https://usir.salford.ac.uk/id/eprint/33628

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