Development of ET, primary myelofibrosis and PV in mice expressing JAK2 V617F.
An acquired JAK2 V617F mutation is found in most patients with polycythemia vera (PV), and about half of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Mice transplanted with bone marrow cells in which JAK2 V617F was retrovirally expressed developed PV-like features, but not ET or PMF. To address the contribution of this mutation to the pathogenesis of these three MPDs, we generated two lines of JAK2 V617F transgenic mice. One line showed granulocytosis after 4 months of age. Among 43 mice, 8 (19%) showed polycythemia and 15 (35%) showed thrombocythemia. The second line showed extreme leukocytosis and thromobocytosis. They showed anemia that means Hb value from 9 to 10 g per 100 ml when 1 month old. Myeloid cells and megakaryocytes were predominant in the bone marrow of these animals, and splenomegaly was observed. The expression of JAK2 V617F mRNA in bone marrow cells was 0.45 and 1.35 that of endogenous wild-type JAK2 in the two lines, respectively. In vitro analysis of bone marrow cells from both lines showed constitutive activation of ERK1/2, STAT5 and AKT, and augmentation of their phosphorylations by cytokine stimulation. We conclude that in vivo expression of JAK2 V617F results in ET-, PMF- and PV-like disease.
Shide
K
K
Department of Gastroenterology and Hematology, Faculty of Medicine, Miyazaki University, Kiyotake, Miyazaki, Japan. kshimoda@med.miyazaki-u.ac.jp
Shimoda
H K
HK
Kumano
T
T
Karube
K
K
Kameda
T
T
Takenaka
K
K
Oku
S
S
Abe
H
H
Katayose
K S
KS
Kubuki
Y
Y
Kusumoto
K
K
Hasuike
S
S
Tahara
Y
Y
Nagata
K
K
Matsuda
T
T
Ohshima
K
K
Harada
M
M
Shimoda
K
K
D000818:Animals; D016026:Bone Marrow Transplantation; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D007964:Leukocytosis / Q000473:pathology; D008297:Male; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D011087:Polycythemia Vera / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055728:Primary Myelofibrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013920:Thrombocythemia, Essential / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D016207:Cytokines; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3