Loss of wild-type Jak2 allele enhances myeloid cell expansion and accelerates myelofibrosis in Jak2V617F knock-in mice.

Content Provider	Europe PMC
Author	Akada, Hajime Akada, Saeko Hutchison, Robert E. Mohi, Golam
Abstract	JAK2V617F is the most common mutation found in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Although a majority of MPN patients carry heterozygous JAK2V617F mutation, loss of heterozygosity (LOH) on chromosome 9p involving the JAK2 locus has been observed in ~30% of MPN patients. JAK2V617F homozygosity via 9pLOH has been associated with more severe MPN phenotype. However, the contribution of 9pLOH in the pathogenesis of MPNs remains unclear. To investigate the roles of wild-type JAK2 (JAK2 WT) and JAK2V617F alleles in the development of MPNs, we have utilized conditional Jak2 knock-out and Jak2V617F knock-in mice and generated heterozygous, hemizygous and homozygous Jak2V617F mice. Whereas heterozygous Jak2V617F expression results in a polycythemia vera-like MPN in mice, loss of Jak2 WT allele in hemizygous or homozygous Jak2V617F mice results in markedly increased white blood cells, neutrophils, reticulocytes and platelets in the peripheral blood, and significantly larger spleen size compared with heterozygous Jak2V617F mice. Hemizygous or homozygous Jak2V617F mice also exhibit accelerated myelofibrosis compared with mice expressing heterozygous Jak2V617F. Together, these results suggest that loss of Jak2 WT allele increases the severity of the MPN. Thus, the Jak2 WT allele functions as a negative regulator of MPN induced by Jak2V617F.
ISSN	08876924
Journal	Leukemia
Volume Number	28
PubMed Central reference number	PMC4117831
Issue Number	8
PubMed reference number	24480985
e-ISSN	14765551
DOI	10.1038/leu.2014.52
Language	English
Publisher Date	2014-01-31
Access Restriction	Open
Rights License	Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
Subject Keyword	Myeloproliferative neoplasms myelofibrosis JAK2 JAK2V617F
Content Type	Text
Resource Type	Article
Subject	Hematology Cancer Research Anesthesiology and Pain Medicine Oncology