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Blood, 1 June 2006, Vol. 107, No. 11, pp. 4274-4281.
Prepublished online as a Blood First Edition Paper on February 14, 2006; DOI 10.1182/blood-2005-12-4824.
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HEMATOPOIESIS
Expression of Jak2V617F causes a polycythemia vera–like disease with associated myelofibrosis in a murine bone marrow transplant model
Gerlinde Wernig,
Thomas Mercher,
Rachel Okabe,
Ross L. Levine,
Benjamin H. Lee, and
D. Gary Gilliland
From the Division of Hematology, Department of Medicine, the Howard Hughes Medical Institute, and the Department of Pathology, Brigham and Women's Hospital, Boston; and the Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
An acquired somatic mutation, Jak2V617F, was recently discovered in most patients with polycythemia vera (PV), chronic idiopathic myelofibrosis (CIMF), and essential thrombocythemia (ET). To investigate the role of this mutation in vivo, we transplanted bone marrow (BM) transduced with a retrovirus expressing either Jak2 wild-type (wt) or Jak2V617F into lethally irradiated syngeneic recipient mice. Expression of Jak2V617F, but not Jak2wt, resulted in clinicopathologic features that closely resembled PV in humans. These included striking elevation in hemoglobin level/hematocrit, leukocytosis, megakaryocyte hyperplasia, extramedullary hematopoiesis resulting in splenomegaly, and reticulin fibrosis in the bone marrow. Histopathologic and flow cytometric analyses showed an increase in maturing myeloid lineage progenitors, although megakaryocytes showed decreased polyploidization and staining for acetylcholinesterase. In vitro analysis of primary cells showed constitutive activation of Stat5 and cytokine-independent growth of erythroid colony-forming unit (CFU-E) and erythropoietin hypersensitivity, and Southern blot analysis for retroviral integration indicated that the disease was oligoclonal. Furthermore, we observed strain-specific differences in phenotype, with Balb/c mice demonstrating markedly elevated leukocyte counts, splenomegaly, and reticulin fibrosis compared with C57Bl/6 mice. We conclude that Jak2V617F expression in bone marrow progenitors results in a PV-like syndrome with myelofibrosis and that there are strain-specific modifiers that may in part explain phenotypic pleiotropy of Jak2V617F-associated myeloproliferative disease in humans.
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[PDF]
|
|
|
|
|
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|
|
|
|
|
|
|
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113(12):
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[Full Text]
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|
|
|
|
|
|
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262 - 271.
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|
|
|
|
|
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94(1):
7 - 10.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Agarwal, T. G. P. Bumm, A. S. Corbin, T. O'Hare, M. Loriaux, J. VanDyke, S. G. Willis, J. Deininger, K. I. Nakayama, B. J. Druker, et al.
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112(5):
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|
|
|
|
|
|
|
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93(7):
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[Full Text]
[PDF]
|
|
|
|
|
|
|
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June 15, 2008;
111(12):
5663 - 5671.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Xing, T. H. Wanting, W. Zhao, J. Ma, S. Wang, X. Xu, Q. Li, X. Fu, M. Xu, and Z. J. Zhao
Transgenic expression of JAK2V617F causes myeloproliferative disorders in mice
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May 15, 2008;
111(10):
5109 - 5117.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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Substitution of Pseudokinase Domain Residue Val-617 by Large Non-polar Amino Acids Causes Activation of JAK2
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283(19):
12941 - 12948.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. B. Lipka, L. S. Hoffmann, F. Heidel, B. Markova, M.-C. Blum, F. Breitenbuecher, S. Kasper, T. Kindler, R. L. Levine, C. Huber, et al.
LS104, a non-ATP-competitive small-molecule inhibitor of JAK2, is potently inducing apoptosis in JAK2V617F-positive cells
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7(5):
1176 - 1184.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Tiedt, H. Hao-Shen, M. A. Sobas, R. Looser, S. Dirnhofer, J. Schwaller, and R. C. Skoda
Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice
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April 15, 2008;
111(8):
3931 - 3940.
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[Full Text]
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|
|
|
|
|
|
|
G. Wernig, J. R. Gonneville, B. J. Crowley, M. S. Rodrigues, M. M. Reddy, H. E. Hudon, C. Walz, A. Reiter, K. Podar, Y. Royer, et al.
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April 1, 2008;
111(7):
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|
|
|
|
|
|
|
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711 - 721.
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[Full Text]
[PDF]
|
|
|
|
|
|
|
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Host genetic variation contributes to phenotypic diversity in myeloproliferative disorders
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March 1, 2008;
111(5):
2785 - 2789.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Antonioli, P. Guglielmelli, G. Poli, C. Bogani, A. Pancrazzi, G. Longo, V. Ponziani, L. Tozzi, L. Pieri, V. Santini, et al.
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January 1, 2008;
93(1):
41 - 48.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. S. Wilkins, W. N. Erber, D. Bareford, G. Buck, K. Wheatley, C. L. East, B. Paul, C. N. Harrison, A. R. Green, and P. J. Campbell
Bone marrow pathology in essential thrombocythemia: interobserver reliability and utility for identifying disease subtypes
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January 1, 2008;
111(1):
60 - 70.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Barosi, G. Bergamaschi, M. Marchetti, A. M. Vannucchi, P. Guglielmelli, E. Antonioli, M. Massa, V. Rosti, R. Campanelli, L. Villani, et al.
JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis
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December 1, 2007;
110(12):
4030 - 4036.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Pardanani, T. L. Lasho, C. Finke, R. A. Mesa, W. J. Hogan, R. P. Ketterling, D. G. Gilliland, and A. Tefferi
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September 1, 2007;
25(9):
2358 - 2362.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Vannucchi, E. Antonioli, P. Guglielmelli, A. Rambaldi, G. Barosi, R. Marchioli, R. M. Marfisi, G. Finazzi, V. Guerini, F. Fabris, et al.
Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia
Blood,
August 1, 2007;
110(3):
840 - 846.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Dupont, A. Masse, C. James, I. Teyssandier, Y. Lecluse, F. Larbret, V. Ugo, P. Saulnier, S. Koscielny, J. P. Le Couedic, et al.
The JAK2 617V>F mutation triggers erythropoietin hypersensitivity and terminal erythroid amplification in primary cells from patients with polycythemia vera
Blood,
August 1, 2007;
110(3):
1013 - 1021.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T.-l. Gu, T. Mercher, J. W. Tyner, V. L. Goss, D. K. Walters, M. G. Cornejo, C. Reeves, L. Popova, K. Lee, M. C. Heinrich, et al.
A novel fusion of RBM6 to CSF1R in acute megakaryoblastic leukemia
Blood,
July 1, 2007;
110(1):
323 - 333.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Wagner-Ballon, D. F. Pisani, T. Gastinne, M. Tulliez, R. Chaligne, C. Lacout, F. Aurade, J.-L. Villeval, P. Gonin, W. Vainchenker, et al.
Proteasome inhibitor bortezomib impairs both myelofibrosis and osteosclerosis induced by high thrombopoietin levels in mice
Blood,
July 1, 2007;
110(1):
345 - 353.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Tefferi
Primary myelofibrosis and its paraneoplastic stromal effects
Haematologica,
May 1, 2007;
92(5):
577 - 579.
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. A. Chabner and T. G. Roberts
The FDA in 2006: Reasons for Optimism
Oncologist,
March 1, 2007;
12(3):
247 - 249.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Malinge, R. Ben-Abdelali, C. Settegrana, I. Radford-Weiss, M. Debre, K. Beldjord, E. A. Macintyre, J.-L. Villeval, W. Vainchenker, R. Berger, et al.
Novel activating JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic leukemia
Blood,
March 1, 2007;
109(5):
2202 - 2204.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Li, M. Xu, S. Xing, W. T. Ho, T. Ishii, Q. Li, X. Fu, and Z. J. Zhao
Erlotinib Effectively Inhibits JAK2V617F Activity and Polycythemia Vera Cell Growth
J. Biol. Chem.,
February 9, 2007;
282(6):
3428 - 3432.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. Scott, W. Tong, R. L. Levine, M. A. Scott, P. A. Beer, M. R. Stratton, P. A. Futreal, W. N. Erber, M. F. McMullin, C. N. Harrison, et al.
JAK2 Exon 12 Mutations in Polycythemia Vera and Idiopathic Erythrocytosis
N. Engl. J. Med.,
February 1, 2007;
356(5):
459 - 468.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Skoda
The Genetic Basis of Myeloproliferative Disorders
Hematology,
January 1, 2007;
2007(1):
1 - 10.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Hoffman and D. Rondelli
Biology and Treatment of Primary Myelofibrosis
Hematology,
January 1, 2007;
2007(1):
346 - 354.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Guglielmelli, R. Zini, C. Bogani, S. Salati, A. Pancrazzi, E. Bianchi, F. Mannelli, S. Ferrari, M.-C. Le Bousse-Kerdiles, A. Bosi, et al.
Molecular Profiling of CD34+ Cells in Idiopathic Myelofibrosis Identifies a Set of Disease-Associated Genes and Reveals the Clinical Significance of Wilms' Tumor Gene 1 (WT1)
Stem Cells,
January 1, 2007;
25(1):
165 - 173.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Delhommeau, S. Dupont, C. Tonetti, A. Masse, I. Godin, J.-P. L. Couedic, N. Debili, P. Saulnier, N. Casadevall, W. Vainchenker, et al.
Evidence that the JAK2 G1849T (V617F) mutation occurs in a lymphomyeloid progenitor in polycythemia vera and idiopathic myelofibrosis
Blood,
January 1, 2007;
109(1):
71 - 77.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Xu, Q. Zhang, J. Luo, S. Xing, Q. Li, S. B. Krantz, X. Fu, and Z. J. Zhao
JAK2V617F: prevalence in a large Chinese hospital population
Blood,
January 1, 2007;
109(1):
339 - 342.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. J. Campbell and A. R. Green
The Myeloproliferative Disorders
N. Engl. J. Med.,
December 7, 2006;
355(23):
2452 - 2466.
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. G.P. Bumm, C. Elsea, A. S. Corbin, M. Loriaux, D. Sherbenou, L. Wood, J. Deininger, R. T. Silver, B. J. Druker, and M. W.N. Deininger
Characterization of Murine JAK2V617F-Positive Myeloproliferative Disease
Cancer Res.,
December 1, 2006;
66(23):
11156 - 11165.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. D. Pardanani, R. L. Levine, T. Lasho, Y. Pikman, R. A. Mesa, M. Wadleigh, D. P. Steensma, M. A. Elliott, A. P. Wolanskyj, W. J. Hogan, et al.
MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients
Blood,
November 15, 2006;
108(10):
3472 - 3476.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Kennedy, F. Barabe, B. J. Patterson, J. Bayani, J. A. Squire, D. L. Barber, and J. E. Dick
Expression of TEL-JAK2 in primary human hematopoietic cells drives erythropoietin-independent erythropoiesis and induces myelofibrosis in vivo
PNAS,
November 7, 2006;
103(45):
16930 - 16935.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. L. Spivak
Animal models of the MPD: lack of the clones
Blood,
September 1, 2006;
108(5):
1427 - 1428.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Lacout, D. F. Pisani, M. Tulliez, F. M. Gachelin, W. Vainchenker, and J.-L. Villeval
JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis
Blood,
September 1, 2006;
108(5):
1652 - 1660.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. L. Levine and G. Wernig
Role of JAK-STAT Signaling in the Pathogenesis of Myeloproliferative Disorders
Hematology,
January 1, 2006;
2006(1):
233 - 239.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Tefferi
Classification, Diagnosis and Management of Myeloproliferative Disorders in the JAK2V617F Era
Hematology,
January 1, 2006;
2006(1):
240 - 245.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
