Overview

Also Known As:Jak2^VF

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. These mice may be useful when studying myeloproliferative neoplasm (MPN).

Donating Investigator

Ann Mullally, Brigham and Women's Hospital--Harvard Medical School

Genetic overview

Genetic Background	Generation
	N10+pN1 (2019-03-15 00:00:00)

Jak2^tm1.2Ble

Allele Type	Gene Symbol	Gene Name
Targeted (Conditional ready (e.g. floxed))	Jak2	Janus kinase 2

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Research Applications

Immunology, Inflammation and Autoimmunity Research
Cell Biology Research
Research Tools

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Base Price

Starting at:

$255.00 Domestic price for female 4-week

333.51 Domestic price for breeder pair

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Details

Detailed Description

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, Jak2^VF 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.

Development

The Jak2^VF targeting vector was designed to insert an inverted mutated exon 14 downstream of endogenous exon 14 of the Janus kinase 2 (Jak2) gene. Specifically, the vector included, from 5’ to 3', a loxP site, endogenous exon 14, a loxP511 site, an inverted exon 14, a second loxP site and a second loxP511 site. The inverted exon 14 was modified to harbor a guanine to thymine substitution (G1849T) at amino acid 617, resulting in a valine to phenylalanine mutation (V617F), commonly found in patients with myeloproliferative neoplasm (MPN). An FRT-flanked neomycin resistance (neo) cassette was placed directly downstream of the second loxP511 site. The construct was electroporated into 129S6/SvEvTac-derived TC-1 embryonic stem (ES) cells. ES cells were injected into blastocysts and resulting chimeras were mated to C57BL/6 mice. Offspring were subsequently bred to ACTB:FLPe mice (Stock No. 005703) to remove the neo cassette and progeny were crossed to remove the Flpe-expressing transgene. Jak2^+/VF mice were bred to C57BL/6NCrl mice for at least 10 generations. Upon arrival at The Jackson Laboratory Repository, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize C57BL/6NJ oocytes (Stock No. 005304).

Control Suggestions

Wild-type from the colony
Noncarrier

Approximate Controls

005304 C57BL/6NJ

Additional Information

Considerations for Choosing Controls

Selected References

Mullally A; Lane SW; Ball B; Megerdichian C; Okabe R; Al-Shahrour F; Paktinat M; Haydu JE; Housman E; Lord AM; Wernig G; Kharas MG; Mercher T; Kutok JL; Gilliland DG; Ebert BL. 2010. Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells. Cancer Cell 17(6):584-96PubMed: 20541703 MGI: J:160883

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Genetics

Jak2^tm1.2Ble

Allele Symbol: Jak2^tm1.2Ble

Allele Name	targeted mutation 1.2, Benjamin L Ebert
Allele Type	Targeted (Conditional ready (e.g. floxed))
Allele Synonym(s)	Jak2^tm1.2Ble; targeted mutation 1.2, Benjamin L Ebert
Gene Symbol and Name	Jak2, Janus kinase 2
Gene Synonym(s)	C81284; expressed sequence C81284; AI504024; THCYT3; JTK10; expressed sequence AI504024; C81284
Strain of Origin	129S6/SvEvTac
Chromosome	19
Molecular Note	A loxP site was inserted upstream of exon 14 and a cassette, consisting of a loxP511 site, a linker, an inverted loxP site, an inverted exon 14 containing a G1849T mutation, an inverted loxP511 site, and an FRT flanked neo selection cassette, was inserted downstream of exon 14 via homologous recombination. The neo cassette was removed by flp mediated recombination. Cre mediated recombination results in the removal of the endogenous exon 14 and the inversion of the mutated exon 14. The G1849T mutation results in a V617F substitution.

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

polycythemia vera

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Immunology, Inflammation and Autoimmunity Research
- Intracellular Signaling Molecules
Cell Biology Research
- Signal Transduction
Research Tools
- Cre-lox System
  - loxP-flanked Sequences

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Jak2^tm1.2Ble/Jak2^tm1.2Ble
involves: 129S6/SvEvTac * C57BL/6 * FVB/N

mortality/aging

prenatal lethality, complete penetrance
- unable to obtain any viable homozygotes, with the stage of prenatal lethality not specified

Genotype: Jak2^tm1.2Ble/Jak2⁺
involves: 129S6/SvEvTac * C57BL/6 * FVB/N

hematopoietic system phenotype

abnormal definitive hematopoiesis
- disproportional increase in the number of erythroid progenitors relative to other myeloid progenitor
- expansion of the megakaryocytic/erythroid progenitor (MEP) population

abnormal erythropoiesis
- increase in the number of erythroid precursors in the bone marrow and spleen
- marked erythroid hyperplasia in the splenic red pulp

abnormal hematopoietic system physiology
- gene set enrichment analysis indicates that hematopoietic differentiation in the LSK compartment is altered
- MEPs show EPO hypersensitivity

abnormal megakaryocyte morphology
- megakaryocytes with atypical nuclear features are present in the bone marrow

abnormal spleen morphology
- overall effacement of the normal architecture

abnormal spleen red pulp morphology
- marked erythroid and mild megakaryocytic hyperplasia in the splenic red pulp

enhanced megakaryocyte emperipolesis
- megakaryocytes with prominent emperipolesis are present in the bone marrow

enlarged spleen

extramedullary hematopoiesis
- prominent splenic extramedullary hematopoiesis

increased erythroid progenitor cell number

increased hematocrit

increased leukocyte cell number

increased megakaryocyte cell number
- mild hyperplasia in the splenic red pulp

immune system phenotype

abnormal spleen morphology
- overall effacement of the normal architecture

abnormal spleen red pulp morphology
- marked erythroid and mild megakaryocytic hyperplasia in the splenic red pulp

enlarged spleen

increased leukocyte cell number

mammalian phenotype

hematopoietic system phenotype
- Normal - despite the increase in megakaryocyte numbers no increases in platelet counts are detected

mortality/aging

premature death
- median survival is 146 days

neoplasm

increased hemolymphoid system tumor incidence
- all develop a myeloproliferative neoplasm
- Normal - however, acute leukemia is not detected
- these myeloproliferative neoplasms can be transplanted by transfer of either unfractionated bone marrow cells or LSK cells but not by transfer of MEP or granulocyte/macrophage progenitor cells

References

Mullally A; Lane SW; Ball B; Megerdichian C; Okabe R; Al-Shahrour F; Paktinat M; Haydu JE; Housman E; Lord AM; Wernig G; Kharas MG; Mercher T; Kutok JL; Gilliland DG; Ebert BL. 2010. Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells. Cancer Cell 17(6):584-96PubMed: 20541703 MGI: J:160883

Additional - Jak2^tm1.2Ble related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Separated PCR:Jak2-Alternate 2
- Sanger sequencing:Jak2 SEQ Alt 2
- Genotyping resources and troubleshooting
Dietary Information
- LabDiet® 5K54 formulation (4% fat)
Breeding Considerations

When maintaining a live colony, heterozygous mice may be bred to wild-type (noncarrier) mice from the colony or to C57BL/6NJ inbred mice (Stock No. 005304). The donating investigator reports that homozygous mice are not viable.
- Additional Breeding and Husbandry Support
Mating System
- Wild-type x Heterozygote
- Heterozygote x Wild-type
Citation
When using the Jak2^VF mouse strain in a publication, please cite the originating article(s) and include JAX stock #031658 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

AX18 (Maximum)

Pricing & Availability

Available

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Breeder Pair

Sex

Genotype

Price

Female
Male

Cryorecovery - Pricing

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	Please inquire

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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Licensing Information

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Also Known As:Jak2VF

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Approximate Controls

Additional Information

Selected References

Jak2tm1.2Ble

Allele Symbol: Jak2tm1.2Ble

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Mammalian Phenotype Terms by Genotype

Genotype: Jak2tm1.2Ble/Jak2tm1.2Bleinvolves: 129S6/SvEvTac * C57BL/6 * FVB/N

mortality/aging

Genotype: Jak2tm1.2Ble/Jak2+involves: 129S6/SvEvTac * C57BL/6 * FVB/N

hematopoietic system phenotype

immune system phenotype

mammalian phenotype

mortality/aging

neoplasm

References

Additional - Jak2tm1.2Ble related

Genotyping Protocols

Dietary Information

Breeding Considerations

Mating System

Citation

Animal Health Reports

Live Mouse

Breeder Pair

Cryorecovery - Pricing

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Also Known As:Jak2^VF

Jak2^tm1.2Ble

Allele Symbol: Jak2^tm1.2Ble

Genotype: Jak2^tm1.2Ble/Jak2^tm1.2Ble
involves: 129S6/SvEvTac * C57BL/6 * FVB/N

Genotype: Jak2^tm1.2Ble/Jak2⁺
involves: 129S6/SvEvTac * C57BL/6 * FVB/N

Additional - Jak2^tm1.2Ble related