Jak2+/VF mice have an inverted exon 14, carrying a valine to phenylalanine mutation (V617F), downstream of the endogenous exon 14 of the Janus kinase 2 (Jak2) gene. Both exons are surrounded by loxP and loxP511 sites, allowing for Cre-mediated removal of the endogenous exon 14 and inversion of the mutated exon 14. The V617F mutation is commonly found in patients with myeloproliferative neoplasm (MPN) and is present in approximately 95% of patients with polycythemia vera (PV) and in approximately 50% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF).
JAK2 is a protein tyrosine kinase involved in a specific subset of cytokine receptor signaling pathways and is misregulated or mutated in some myeloproliferative diseases and cancers. The V617F mutation results in constitutive activation of JAK2 kinase signaling. When activated, JAK2 phosphorylates STAT transcription factors and initiates the JAK-STAT signaling pathway. This is the most prevalent JAK2 mutation.
Mice that are heterozygous for this allele are viable and fertile, while floxed homozygous mice are not viable. Lethality may be the result of the targeting construct creating a null allele prior to cre excision. When bred to mice that express tissue-specific Cre recombinase, resulting offspring will have the floxed endogenous exon 14 removed and the V617F mutant exon 14 placed into transcriptional orientation.
When mice are bred to a germline or a hematopoietic-specific Cre Recombinase expressing strain such as B6.FVB-Tg(EIIa-cre)C5379Lmgd/J (Stock No. 003724), B6.Cg-Tg(Mx1-cre)1Cgn/J (Stock No. 003556), or VavCre, mice are a model of MPN characterized by elevated hematocrit (HCT), splenomegaly, and prominent splenic extramedullary erythropoiesis. Mice have median survival time of 146 days. They develop lethal 100% penetrant myeloproliferative neoplasms but not acute leukemia. The bone marrow myeloid progenitor compartment is skewed toward the erythroid lineage, which cannot transfer disease. The long-term HSC compartment (CD150+ CD48+ LSK) can transplant the disease into lethally irradiated wild-type recipient mice. When mice are treated with Interferon-α, Jak2VF MPN-propagating cells are depleted, and the disease cannot be transferred.
Of note crossing primary floxed mice to MxCre results in spontaneous recombination in the absence of pIpC.
