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; Chen, E; Saeb-Parsy, K; Fink, J; Sneade, R; Hamilton, TL; Pask, DC; Silber, Y; Zhao, X; Ghevaert, C; Liu, P; Green, AR

Abstract

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.

Citation

Li, J., Kent, D., Godfrey, A., Manning, H., Nangalia, J., Aziz, A., …Green, A. (2014). JAK2V617F homozygosity drives a phenotypic switch in myeloproliferative neoplasms, but is insufficient to sustain disease. Blood, 123(20), 3139-3151. https://doi.org/10.1182/blood-2013-06-510222

• Journal Article Type: Article
• Acceptance Date: Feb 28, 2014
• Online Publication Date: May 15, 2014
• Publication Date: Apr 1, 2014
• Deposit Date: Jan 30, 2015
• Journal: Blood
• Print ISSN: 0006-4971
• Electronic ISSN: 1528-0020
• Publisher: American Society of Hematology
• Peer Reviewed: Peer Reviewed
• Volume: 123
• Issue: 20
• Pages: 3139-3151
• DOI: https://doi.org/10.1182/blood-2013-06-510222
• Publisher URL: http://dx.doi.org/10.1182/blood-2013-06-510222