Abstract

JAK2V617F, a mutant form of tyrosine kinase JAK2, is found in the majority of patients with myeloproliferative disorders (MPDs). It displays increased kinase activity and causes MPD phenotypes in transgenic mice in a transgence dosage-dependent manner. Following our initial generation and characterization of JAK2V617F transgenic mice, we further generated transgenic mice expressing wild type JAK2 by using the same vav promoter employed for JAK2V617F. Three lines of JAK2 transgenic mice were generated. Real time PCR analyses revealed transgene copy numbers of 38, 2, and 1. All these mice are viable and fertile, and they displayed normal blood cell counts. This proves that the V617F mutation but not gene overexpression per se caused MPD phenotypes in JAK2V617F transgenic mice. We then crossed the JAK2 and JAK2V617F transgenic mice to generate JAK2/JAK2V617F double transgenic hybrids. Interestingly, these hybrid mice developed no or mild MPD phenotypes with only a slight increase in blood counts in contrast to the striking elevation observed in JAK2V617F transgenic mice. Expression of wild type JAK2 also blocked the constitutive activation of signal transduction components caused by JAK2V617F. Our data indicates that over-expression of wild type JAK2 suppresses the pathogenic function of mutant JAK2V617F. Therefore, JAK2V617F is not a typical dominant oncogene. Homozygous mutation or in the case of heterozygous mutation, its amplification with concurrent deletion or suppression of wild type JAK2, is required to produce MPD phenotypes. Our transgenic mouse models will serve as an invaluable tool to study the interplay of JAK2 and JAK2V617F and the mechanism by which specific MPD phenotypes develop.

Disclosures: No relevant conflicts of interest to declare.

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