Are you looking to advance your understanding of myeloproliferative neoplasms (MPNs) and their genetic underpinnings? The JAK2*V617F mutant mouse model offers researchers an unparalleled tool to study the mechanisms behind genetically-linked diseases like polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Featuring the most common mutation found in MPNs, this cutting-edge model replicates the disease’s hallmark characteristics, including abnormal blood cell production and splenomegaly.

In this article, we’ll explore the unique features of the JAK2*V617F mutant mouse, its role in MPN research, and how it can accelerate your preclinical studies. Read on to see how this model can transform your investigations into hematologic disorders and accelerate drug development.

What Are Myeloproliferative Neoplasms (MPNs)?

Myeloproliferative neoplasms (MPNs) are a group of chronic hematologic malignancies (blood cancers) characterized by the excessive proliferation of blood cells, often accompanied by splenomegaly, thrombosis, and a tendency to bleed. Common types include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (MF). Among MPNs, the JAK2V617F mutation is the most common driver gene mutation, found in approximately 95% of PV patients and 50-60% of ET and MF patients.[1] 

This mutation occurs in the JH2 pseudokinase domain of the tyrosine kinase encoded by the JAK2 gene, leading to constitutive activation of tyrosine kinase activity. The result is abnormal hematopoiesis and bone marrow fibrosis (myelofibrosis), hallmarks of MPN pathogenesis.

To advance MPN research, Cyagen has developed the Jak2*V617F mutant mouse model, which replicates key pathological features of human MPN, offering a robust platform for studying disease mechanisms and developing therapies.

Figure 1. The JAK2*V617F mutation is the most common genetic driver in the three major types of MPN: PV, ET, and MF. [1]

Understanding Myeloproliferative Neoplasms and JAK2*V617F Mutation

Overview of Myeloproliferative Neoplasms (MPNs)

MPNs are chronic blood disorders with an incidence rate of 0.5-2 per 100,000 people per year, characterized by the excessive production of one or more mature myeloid blood cells.[2] Its clinical manifestations include splenomegaly, thrombosis, and bleeding, and approximately 5% of patients may progress to acute myeloid leukemia (AML). MPN can be classified into Philadelphia chromosome (Ph)-positive blood cancers or Ph-negative disorders based on the presence of the Ph translocation:

  • Ph-positive MPN: Chronic myeloid leukemia (CML).
  • Ph-negative MPN: A group of hematological disorders that are characterized by abnormal production of mature bone marrow cells. Examples include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (MF).


Key clinical features of Ph-negative MPNs include:

  • PV: Elevated red blood cell production (erythrocytosis) and hyperplasia of all myeloid lineages (panmyelosis), often with increased neutrophils (neutrophilia) and platelets.[2-3]
  • ET: Excessive platelet production (thrombocytosis).
  • PMF: Advanced MPN marked by collagen deposition in the bone marrow, peripheral cytopenia, leukocytosis, erythrocytosis, splenomegaly, and systemic symptoms.


Ph-negative MPN is genetically linked, with most patients carrying the JAK2*V617F mutation—which is caused by a G to T single nucleotide substitution at codon 1849 of exon 14 of the JAK2 gene (c.1849G>T), resulting in a valine (V) to phenylalanine (F) substitution at amino acid position 617 of the JAK2 protein.[3-4] This mutation confers cytokine-independent activation of JAK-STAT signaling pathways, driving excessive red blood cell, platelet, and granulocyte production, leading to symptoms such as thrombosis and splenomegaly.

Figure 2. Classification of Myeloproliferative Neoplasms (MPN). [5]

The Role of JAK2 in Hematopoiesis

The Janus kinase 2 (JAK2) protein plays a crucial role in normal hematopoiesis by participating in the signaling of various cytokines—such as erythropoietin, thrombopoietin, granulocyte colony-stimulating factor, interleukins, and interferons. It activates STAT proteins, promoting the proliferation and differentiation of blood cells.[6-7] JAK2 is essential for erythropoiesis, megakaryopoiesis, and granulopoiesis, ensuring the proper development and maintenance of various blood cell lineages.

The JAK2V617F mutation is the most common pathogenic mutation in human MPN, detected in 50%-60% of ET and PMF patients, and in more than 95% of PV patients. The conformational change caused by the JAK2V617F mutation enhances the catalytic activity of JAK2, keeping it in a continuously activated state, which allows it to activate downstream signaling pathways without the need for cytokine ligand binding. This mutation causes:

  • Uncontrolled activation of downstream pathways such as STAT, MAPK, and PI3K/AKT, leading to abnormal proliferation;
  • Dysregulation of signaling pathways, including JAK-STAT, MAPK, and PI3K/AKT, further driving the abnormal proliferation and differentiation of hematopoietic cells;
  • Enhanced hematopoietic activity - excessive production of red blood cells, platelets, and granulocytes - independent of cytokine stimulation;
  • Above factors cumulatively lead to hematopoietic abnormalities and typical MPN symptoms such as thrombosis and splenomegaly.[6-7] 


This mutation is often found in conjunction with other gene mutations (e.g., MPL or CALR), accelerating disease progression. [7-8]

Figure 3. The Function of JAK2 in Normal Hematopoiesis and the Mechanism by Which the JAK2*V617F Variant Leads to MPN. [8]

Cyagen's Jak2*V617F Mutant Mouse Model for MPN Disease Research

To promote MPN research, Cyagen has independently developed a range of JAK2*V617F mouse models, including the Jak2*V617F mutant mouse model with an in situ mutation of the Jak2 gene (Product ID: C001564). This disease-specific mutant model aims to mimic key pathological features of MPN observed in humans by introducing a mutation homologous to the human JAK2*V617F into the mouse genome using advanced genetic engineering techniques. Below are the main phenotypes of the Jak2*V617F mice.

Note: Due to the lethal effects of homozygosity, all phenotypic validations are based on heterozygous mice.

Multilineage Hematopoietic Dysplasia

Compared to wild-type mice, Jak2*V617F mice exhibit significant hyperplasia alongside elevated erythroid, granulocytic, and megakaryocytic hematopoiesis. Hematological tests show a significant increase in red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT), white blood cell count (WBC), and platelet count (PLT).

Figure 4. Hematological Analysis of Wild-Type (WT) Mice and Jak2*V617F Mice (Male, 10 Weeks Old).

Splenomegaly

Dissection reveals that Jak2*V617F mice have significantly enlarged spleens with a notable increase in weight.

Figure 5. Comparison of Spleen Appearance and Weight Between Wild-Type (WT) Mice and Jak2*V617F Mice (Male, 10 Weeks Old).

Histopathological Changes in the Spleen

Histological analysis shows that, compared to wild-type mice, Jak2*V617F mice have significantly swollen spleens with structural damage, characterized by myeloid cell hyperplasia and marked megakaryocytic proliferation, along with extramedullary hematopoiesis and congestion of the splenic sinusoids.

Figure 6. Comparison of Spleen H&E Staining Results Between Wild-Type (WT) Mice and Jak2*V617F Mice (10 Weeks Old).

Jak2*V617F Mouse Model: Summary of Key Features and Phenotypes

  • Multilineage Hematopoietic Abnormalities:
    • Significant proliferation of erythroid, granulocyte, and megakaryocyte lineages.
    • Elevated red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT), white blood cell count (WBC), and platelet count (PLT).
  • Splenomegaly:
    • Markedly enlarged spleens, with increased spleen weight.
  • Histopathological Changes:
    • Disrupted splenic architecture.
    • Myeloid cell proliferation, extramedullary hematopoiesis, and splenic sinusoid congestion.

Research Applications and Benefits

The Jak2*V617F mouse model is ideal for:

  • Investigating the molecular mechanisms underlying PV, ET, and PMF.
  • Evaluating potential therapeutic interventions targeting MPN.
  • Modeling disease progression and drug responses in preclinical studies.


In addition to this model, Cyagen is currently validating a JAK2*V617F humanized  mouse model expressing the V617F-mutated human JAK2 gene following Cre recombinase induction (currently in the phenotype validation stage).

Conclusion

The Jak2*V617F mouse (Product ID: C001564), carrying the human JAK2V617F homologous mutation, exhibits typical phenotypes of genetically-linked myeloproliferative neoplasms (MPN), including splenomegaly, multilineage (erythroid, granulocytic, and megakaryocytic) hematopoietic hyperplasia, extramedullary hematopoiesis, and congestion of splenic sinusoids. It is an ideal model for studying the mechanisms of chronic inherited diseases such as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), as well as for therapeutic drug development.

For more information about the Jak2*V617F mutant mouse model or the JAK2*V617F genomic mutant humanized mouse model currently under-development, please contact us.

Since 2006, Cyagen has provided a comprehensive portfolio of custom animal modeling capabilities, including hereditary, inducible, and transplantable mouse models. In addition, Cyagen offers a variety of genetic, inducible, and transplant models for research in hematological diseases, oncology, and numerous other research fields.

 

References:
[1]Nangalia J, Grinfeld J, Green AR. Pathogenesis of Myeloproliferative Disorders. Annu Rev Pathol. 2016 May 23;11:101-26.
[2]Passamonti F, Mora B. Myelofibrosis. Blood. 2023 Apr 20;141(16):1954-1970.
[3]Spivak JL. Myeloproliferative Neoplasms. N Engl J Med. 2017 Jun 1;376(22):2168-2181.
[4]Luque Paz D, Kralovics R, Skoda RC. Genetic basis and molecular profiling in myeloproliferative neoplasms. Blood. 2023 Apr 20;141(16):1909-1921.
[5]TeachIM. "Myeloproliferative Neoplasms." TeachingIM, https://teachim.org/teaching_material/mpn-2/. Accessed 24 October 2024.
[6]Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. 2007 Sep;7(9):673-83.
[7]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.
[8]Gou P, Zhang W, Giraudier S. Insights into the Potential Mechanisms of JAK2V617F Somatic Mutation Contributing Distinct Phenotypes in Myeloproliferative Neoplasms. Int J Mol Sci. 2022 Jan 18;23(3):1013.

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