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 Blood, 15 April 2008, Vol. 111, No. 8, pp. 3931-3940.
Prepublished online as a Blood First Edition Paper on December 26, 2007; DOI 10.1182/blood-2007-08-107748.

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PLENARY PAPER

Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice

Ralph Tiedt1, Hui Hao-Shen1, Marta A. Sobas1,2, Renate Looser1, Stephan Dirnhofer3, Jürg Schwaller4, and Radek C. Skoda1

1 Department of Research, Experimental Hematology, University Hospital Basel, Basel, Switzerland; 2 Servicio de Hematologia y Hemoterapia, Hospital Clinico Universitario de Santiago de Compostela, Santiago de Compostela, Spain; 3 Institute of Pathology, University Hospital Basel, Basel, Switzerland; and 4 Department of Research, Childhood Leukemia, University Hospital Basel, Basel, Switzerland

An acquired somatic mutation in the JAK2 gene (JAK2-V617F) is present in the majority of patients with myeloproliferative disorders (MPDs). Several phenotypic manifestations (polycythemia vera [PV], essential thrombocythemia [ET], and primary myelofibrosis) can be associated with the same mutation. We generated JAK2-V617F transgenic mice using a human JAK2 gene with the sequences encoding the kinase domain placed in the inverse orientation and flanked by antiparallel loxP sites. Crossing mice of one transgenic line (FF1) with transgenic mice expressing Cre-recombinase under the control of the hematopoiesis specific Vav promoter led to expression of JAK2-V617F that was lower than the endogenous wild-type Jak2. These mice developed a phenotype resembling ET with strongly elevated platelet counts and moderate neutrophilia. Induction of the JAK2-V617F transgene with the interferon-inducible MxCre resulted in expression of JAK2-V617F approximately equal to wild-type Jak2 and a PV-like phenotype with increased hemoglobin, thrombocytosis, and neutrophilia. Higher levels of JAK2-V617F in mouse bone marrow by retroviral transduction caused a PV-like phenotype without thrombocytosis. These data are consistent with the hypothesis that the ratio of mutant to wild-type JAK2 is critical for the phenotypic manifestation. A similar correlation was also found in patients with MPD.


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