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


Autoři: Emilie A. Chapeau aff001;  Emeline Mandon aff001;  Jason Gill aff002;  Vincent Romanet aff001;  Nicolas Ebel aff001;  Violetta Powajbo aff001;  Rita Andraos-Rey aff001;  Zhiyan Qian aff001;  Miltos Kininis aff001;  Sabine Zumstein-Mecker aff001;  Moriko Ito aff001;  Nancy E. Hynes aff002;  Ralph Tiedt aff001;  Francesco Hofmann aff001;  Leonid Eshkind aff003;  Ernesto Bockamp aff003;  Bernd Kinzel aff004;  Matthias Mueller aff004;  Masato Murakami aff001;  Fabienne Baffert aff001;  Thomas Radimerski aff001
Působiště autorů: Disease Area Oncology, Novartis Institutes for BioMedical Research, Basel, Switzerland aff001;  Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland aff002;  Institute for Translational Immunology and Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany aff003;  Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, Basel, Switzerland aff004
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0221635

Souhrn

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.

Klíčová slova:

Bone marrow – Bone marrow cells – Bone marrow transplantation – Cloning – Mouse models – Phenotypes – Platelets – Spleen


Zdroje

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