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A conditional inducible JAK2V617F transgenic mouse model reveals myeloproliferative disease that is reversible upon switching off transgene expression.
- Source :
-
PloS one [PLoS One] 2019 Oct 10; Vol. 14 (10), pp. e0221635. Date of Electronic Publication: 2019 Oct 10 (Print Publication: 2019). - Publication Year :
- 2019
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Abstract
- Aberrant activation of the JAK/STAT pathway is thought to be the critical event in the pathogenesis of the chronic myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia and primary myelofibrosis. The most frequent genetic alteration in these pathologies is the activating JAK2V617F mutation, and expression of the mutant gene in mouse models was shown to cause a phenotype resembling the human diseases. Given the body of genetic evidence, it has come as a sobering finding that JAK inhibitor therapy only modestly suppresses the JAK2V617F allele burden, despite showing clear benefits in terms of reducing splenomegaly and constitutional symptoms in patients. To gain a better understanding if JAK2V617F is required for maintenance of myeloproliferative disease once it has evolved, we generated a conditional inducible transgenic JAK2V617F mouse model using the SCL-tTA-2S tet-off system. Our model corroborates that expression of JAK2V617F in hematopoietic stem and progenitor cells recapitulates key hallmarks of human myeloproliferative neoplasms, and exhibits gender differences in disease manifestation. The disease was found to be transplantable, and importantly, reversible when transgenic JAK2V617F expression was switched off. Our results indicate that mutant JAK2V617F-specific inhibitors should result in profound disease modification by disabling the myeloproliferative clone bearing mutant JAK2.<br />Competing Interests: Some of the authors are full-time employees of Novartis Pharma AG (Emilie A. Chapeau, Emeline Mandon, Vincent Romanet, Nicolas Ebel, Rita Andraos-Rey, Zhiyan Qian, Miltos Kininis, Sabine Zumstein-Mecker, Ralph Tiedt, Francesco Hofmann, Matthias Mueller, Fabienne Baffert), or have been full-time employees of Novartis Pharma AG (Violetta Powajbo, Moriko Ito, Bernd Kinzel, Masato Murakami, Thomas Radimerski). Novartis Pharma AG had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Ruxolitinib is a marketed product of Incyte, for which Novartis Pharma AG received exclusive development and commercialization rights outside of the United States. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
- Subjects :
- Amino Acid Substitution
Animals
Disease Models, Animal
Humans
Mice
Mice, Transgenic
Mutation, Missense
Gene Expression Regulation
Hematopoietic Stem Cells metabolism
Hematopoietic Stem Cells pathology
Janus Kinase 2 biosynthesis
Janus Kinase 2 genetics
Myeloproliferative Disorders genetics
Myeloproliferative Disorders metabolism
Myeloproliferative Disorders pathology
Transgenes
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 14
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 31600213
- Full Text :
- https://doi.org/10.1371/journal.pone.0221635