A conditional inducible JAK2V617F transgenic mouse model reveals myeloproliferative disease that is reversible upon switching off transgene expression.

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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.
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Authors Chapeau, Emilie A;Mandon, Emeline;Gill, Jason;Romanet, Vincent;Ebel, Nicolas;Powajbo, Violetta;Andraos-Rey, Rita;Qian, Zhiyan;Kininis, Miltos;Zumstein-Mecker, Sabine;Ito, Moriko;Hynes, Nancy E;Tiedt, Ralph;Hofmann, Francesco;Eshkind, Leonid;Bockamp, Ernesto;Kinzel, Bernd;Mueller, Matthias;Murakami, Masato;Baffert, Fabienne;Radimerski, Thomas;
Journal PloS one
Year 2019
DOI
10.1371/journal.pone.0221635
URL
Keywords
Migration virulence dissemination toxoplasma gondii cyst crispr actin wave complex dendritic cell motility loss-of-function screen

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