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Real-time bioluminescence imaging of polycythemia vera development in mice
Yanhong Ma1, Shuxia Zhao, Joe Zhu
1Department of Oncology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Abstract:
Polycythemia vera (PV) is a myeloproliferative disorder involving hematopoietic stem cells. A recurrent somatic missense mutation in JAK2 (JAK2V617F) is thought to play a causal role in PV. Therefore, targeting Jak2 will likely provide a molecular mechanism-based therapy for PV. To facilitate the development of such new and specific therapeutics, a suitable and well-characterized preclinical animal model is essential. Although several mouse models of PV have been reported, the spatiotemporal kinetics of PV formation and progression has not been studied. To address this, we created a bone marrow transplant mouse model that co-expresses mutant Jak2 and luciferase 2 (Luc2) genes. Bioluminescent imaging (BLI) was used to visualize disease cells and analyze the kinetics of PV development in vivo. To better understand the molecular mechanism of PV, we generated mice carrying a kinase inactive mutant Jak2 (Jak2K882E), demonstrating that the PV disease was dependent on constitutive activation of the Jak2 kinase activity. We further showed that the Jak2V617F mutation caused increased stem cell renewal activity and impaired cell differentiation, which was at least in part due to deregulated transcriptional programming. The Jak2V617F-Luc2 PV mice will be a useful preclinical model to characterize novel JAK2 inhibitors for the treatment of PV.
Insights
Researchers developed a novel mouse model for Polycythemia vera (PV) using bioluminescent imaging to track disease progression. This model aids in developing targeted JAK2 therapies for PV patients.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Polycythemia vera (PV) is a myeloproliferative disorder linked to JAK2V617F mutation.
- Targeting JAK2 offers a potential therapeutic strategy for PV.
- Existing mouse models lack detailed spatiotemporal analysis of PV progression.
Purpose of the Study:
- To develop and characterize a novel preclinical mouse model for PV.
- To investigate the spatiotemporal kinetics of PV development and progression.
- To elucidate the molecular mechanisms underlying JAK2-driven PV.
Main Methods:
- Created a bone marrow transplant mouse model co-expressing mutant JAK2 and luciferase 2 (Luc2).
- Utilized bioluminescent imaging (BLI) for in vivo visualization and kinetic analysis of disease cells.
- Generated mice with a kinase-inactive JAK2 mutant (Jak2K882E) to assess kinase activity dependence.
Main Results:
- The JAK2V617F mutation drives PV pathogenesis, dependent on constitutive kinase activity.
- BLI enabled visualization and kinetic tracking of PV development in vivo.
- JAK2V617F mutation leads to increased stem cell renewal and impaired differentiation, linked to transcriptional dysregulation.
Conclusions:
- The JAK2V617F-Luc2 mouse model is a valuable tool for studying PV.
- This model facilitates the preclinical characterization of novel JAK2 inhibitors for PV treatment.
- Understanding JAK2's role in stem cell dynamics is crucial for PV therapeutic development.
