Loss of wild-type Jak2 allele enhances myeloid cell expansion and accelerates myelofibrosis in Jak2V617F knock-in mice.
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 (9pLOH) 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 used 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.
Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA.
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Akada
Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA.
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Akada
Department of Pathology, SUNY Upstate Medical University, Syracuse, NY, USA.
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Hutchison
Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA.
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Mohi
D000483:Alleles; D000818:Animals; D002899:Chromosomes, Human, Pair 9; D055879:Gene Knock-In Techniques; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D019656:Loss of Heterozygosity; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000473:pathology*; D055728:Primary Myelofibrosis / Q000209:etiology / Q000235:genetics*
C507926:Jak2 protein, mouse; D053614:Janus Kinase 2