Jak2*V617F Mice

Catalog Number: C001564

Strain Name: C57BL/6JCya-Jak2em1(V617F)/Cya

Genetic Background: C57BL/6JCya

Reproduction: Heterozygote x WT

 

Strain Description

Janus kinase 2 (JAK2) is a non-receptor tyrosine kinase that plays a crucial role in the JAK/STAT signaling pathway, which transmits extracellular signals to the nucleus, promoting cell proliferation and division [1]. Myeloproliferative neoplasms (MPNs) are a group of hematological malignancies characterized by the continuous clonal proliferation of one or more relatively mature bone marrow cell lineages. Classic MPNs include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), all of which originate from the clonal expansion of a single hematopoietic stem cell with a somatic mutation, leading to single-lineage or multilineage hyperplasia [2]. The JAK2 V617F mutation is the most common pathogenic mutation in human MPNs. It results from a single nucleotide substitution of G to T at position 1849 in exon 14 of the JAK2 gene (c.1849G>T), causing a valine to phenylalanine substitution (p.V617F) [3]. This dominant gain-of-function (GOF) mutation affects the JH2 pseudokinase domain of JAK2, disrupting its autoinhibitory function, and leading to constitutive activation of JAK2 and the JAK/STAT pathway in the absence of a ligand. The JAK2 V617F mutation is detected in 50%-60% of ET and PMF patients and more than 95% of PV patients [4]. In PV, the mutation causes excessive red blood cell production, increasing blood viscosity and thrombotic risk. In ET, it leads to excessive platelet production, which also increases thrombotic risk. In PMF, it causes bone marrow fibrosis and abnormal blood cell production, leading to anemia, splenomegaly, and other complications [3-4].

The Jak2*V617F mice are generated by introducing a homologous mutation to the human JAK2 V617F into the mouse Jak2 gene via gene editing. This strain is homozygous lethal. Heterozygous Jak2*V617F mice exhibit classic MPN-like disease phenotypes such as splenomegaly and structural damage, significantly elevated red blood cell count, hemoglobin, hematocrit, white blood cell count, platelet count, marked megakaryocytic hyperplasia (with granulocytic and erythroid hyperplasia), extramedullary hematopoiesis, and congestion of splenic sinusoids. Therefore, Jak2*V617F mice can be used for studying the mechanisms of myeloproliferative neoplasms (MPNs) like polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), as well as for evaluating therapeutic drugs.

Strain Strategy

Introducing the p.V617F (GTC to TTC) mutation into exon 14 of the mouse Jak2 gene via gene editing.


Application

  • Research on JAK/STAT signaling pathway transduction;
  • Research on Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF);
  • Development and evaluation of therapeutic drugs for myeloproliferative neoplasms (MPNs).

 

Validation Data

1. Complete Blood Count (CBC) test


Figure 1. Complete Blood Count (CBC) results for wild-type (WT) mice and Jak2*V617F mice (male, 10 weeks old)*. Compared to wild-type mice, Jak2*V617F mice show significant increases in red blood cell count (RBC), hemoglobin (HGB), and hematocrit (HCT), as well as significant increases in white blood cell count (WBC) and platelet count (PLT). These elevated indicators are characteristic of myeloproliferative neoplasms (MPNs), indicating that Jak2*V617F mice exhibit significant MPN disease phenotypes (n=10, ***P < 0.001).

Note: This strain is homozygous lethal, and the validation data for Jak2*V617F mice presented in this document are obtained from heterozygous mice.

2. Appearance and weight of the spleen


Figure 2. Comparison of spleen appearance and weight between wild-type (WT) mice and Jak2*V617F mice (male, 10 weeks old). Dissection result shows that compared to wild-type mice, Jak2*V617F mice have significantly enlarged spleens with increased weight (n=3, **P < 0.01).

3. H&E staining of the spleen


Figure 3. Comparison of H&E staining results in the spleens of wild-type (WT) mice and Jak2*V617F mice (10 weeks old). Compared to wild-type mice, Jak2*V617F mice display splenic swelling, structural damage, and varying degrees of myeloid cell hyperplasia. Specifically, there is a marked increase in megakaryocytes with abundant cytoplasm and large, single or lobulated nuclei (blue arrows). Surrounding these are increased granulocytes of various stages, medium-sized cells with variable cytoplasm amounts, and nuclei that are round or oval, with mature granulocytes showing rod-shaped or lobulated nuclei. Also evident are increases in granulocytes and/or erythroid islands (hematopoietic center islands, yellow arrows), accompanied by an increase in platelets. Additionally, there is splenic sinus congestion and fibrous trabeculae proliferation (green arrows), among other pathologies.



References

[1]Perner F, Perner C, Ernst T, Heidel FH. Roles of JAK2 in Aging, Inflammation, Hematopoiesis and Malignant Transformation. Cells. 2019 Aug 8;8(8):854.
[2]Hyjek E, Vardiman JW. Myelodysplastic/myeloproliferative neoplasms. Semin Diagn Pathol. 2011 Nov;28(4):283-97.
[3]Chen E, Mullally A. How does JAK2V617F contribute to the pathogenesis of myeloproliferative neoplasms? Hematology Am Soc Hematol Educ Program. 2014 Dec 5;2014(1):268-76.
[4]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. Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells. Cancer Cell. 2010 Jun 15;17(6):584-96.