Transgenic mice overexpressing murine thrombopoietin develop myelofibrosis and osteosclerosis

Kakumitsu, Haruko; Kamezaki, Kenjirou; Shimoda, Kazuya; Karube, Kennosuke; Haro, Takashi; Numata, Akihiko; Shide, Kotaro; Matsuda, Tadashi; Oshima, Kouichi; Harada, Mine

doi:10.1016/j.leukres.2004.12.009

Cited by 52 publications

(32 citation statements)

References 32 publications

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“…For example, mice that over-express the megakaryocytic growth factor thrombopoietin, 37 or mice that express low levels of the megakaryocytic transcription factor GATA-1, 38 develop a primary myelofibrosis-like phenotype and, like NFAT2-deficient mice, do not display any gross abnormalities below the age of 12 months. As in human primary myelofibrosis, the genetic defect of these mice points towards a hematopoietic cell (especially the megakaryocyte) as the origin of the stromal abnormalities.…”

Section: Discussionmentioning

confidence: 99%

Osteomyelosclerosis, anemia and extramedullary hematopoiesis in mice lacking the transcription factor NFATc2

Bauer¹,

Rauner²,

Haase³

et al. 2011

Haematologica

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Section: Discussionmentioning

confidence: 99%

Osteomyelosclerosis, anemia and extramedullary hematopoiesis in mice lacking the transcription factor NFATc2

Bauer¹,

Rauner²,

Haase³

et al. 2011

Haematologica

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“…Transgenic mice were produced by standard oocyte injection using BDF1 mouse-derived fertilized eggs. 25 All procedures were approved by the Local Miyazaki University Ethics Committee. Transgenic mice were identified by PCR using oligonucleotide primers specific for the murine JAK2 cDNA (Primer-1, 5…”

Section: Generation Of Transgenic Micementioning

confidence: 99%

“…38 We have previously shown that transgenic mice expressing TPO developed myelofibrosis, and their serum transforming growth factor-b1 and osteoprotegerin levels were high. 25 It is therefore tempting to speculate that the increased numbers of megakaryocytes in line 2 mice are responsible for the production of cytokines that induce myelofibrosis and osteosclerosis. In addition, dysfunction of megakaryocytes can be responsible for transforming growth factor-b1 release; as dysmegakaryopoiesis was observed in JAK2 V617F transgenic mice, both mechanisms might be involved.…”

Section: Jak2 V617f Causes Classical Mpdsmentioning

confidence: 99%

Development of ET, primary myelofibrosis and PV in mice expressing JAK2 V617F

et al. 2007

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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.

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“…Several lines of evidence obtained from both studies of patients with PMF and of murine models ending with myelofibrosis are in favor of a crucial role (i) of the pleiotropic cytokine transforming growth factor ␤1 (TGF-␤1), 13 released by clonal proliferation of megakaryocytes or monocytes or both, in reticulin fiber deposition [14][15][16][17] ; (ii) and of stroma-derived osteoprotegerin (OPG) in osteosclerosis development. [17][18][19] The NF-B pathway, shown to contribute to hematopoietic differentiation, 20 may be involved in the abnormal release of these cytokines.…”

Section: Introductionmentioning

confidence: 99%

“…[17][18][19] The NF-B pathway, shown to contribute to hematopoietic differentiation, 20 may be involved in the abnormal release of these cytokines. Rameshwar et al 21 first reported a spontaneous activation of NF-B in monocytes from PMF patients leading to IL-1 production, which induces TGF-␤1 production through autocrine means.…”

Section: Introductionmentioning

confidence: 99%

Proteasome inhibitor bortezomib impairs both myelofibrosis and osteosclerosis induced by high thrombopoietin levels in mice

Wagner-Ballon

Pisani

Gastinne

et al. 2007

Blood

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Primary myelofibrosis (PMF) is the most serious myeloproliferative disorder, characterized by clonal myeloproliferation associated with cytokine-mediated bone marrow stromal reaction including fibrosis and osteosclerosis. Current drug therapy remains mainly palliative. Because the NF-B pathway is implicated in the abnormal release of cytokines in PMF, the proteasome inhibitor bortezomib might be a potential therapy. To test its effect, we used the lethal murine model of myelofibrosis induced by thrombopoietin (TPO) overexpression. In this TPO high model, the development of the disease is related to a deregulated MPL signaling, as recently described in PMF patients. We first demonstrated that bortezomib was able to inhibit TPO-induced NF-B activation in vitro in murine megakaryocytes. It also inhibited NF-B activation in vivo in TPO high mice leading to decreased IL-1␣ plasma levels. After 4 weeks of treatment, bortezomib decreased TGF-␤1 levels in marrow fluids and impaired marrow and spleen fibrosis development. After 12 weeks of treatment, bortezomib also impaired osteosclerosis development through osteoprotegerin inhibition. Moreover, this drug reduced myeloproliferation induced by high TPO level. Finally, bortezomib dramatically improved TPO high mouse survival (89% vs 8% at week 52). We conclude that bortezomib appears as a promising therapy for future treatment of PMF patients. IntroductionPrimary myelofibrosis (PMF) is a myeloproliferative disorder 1 known as a clonal stem-cell disorder, whereas the associated stromal reaction in the bone marrow environment, leading to fibrosis (excessive deposits of extracellular matrix proteins) and osteosclerosis (new bone formation), is considered to be reactive and cytokine mediated. 2,3 Because the description of mice overexpressing thrombopoietin (TPO), known as TPO high mice, 4 featuring numerous aspects of the human disease including dysmegakaryopoiesis, the implication of the TPO/MPL pathway in PMF has been demonstrated. Recently, two activating mutations of the TPO receptor MPL, MPL W515L and MPL W515K , have been detected in 5% of PMF patients and have been shown to induce fibrosis in mice. 5,6 Activated MPL is known to stimulate the members of the Janus family of protein tyrosine kinases, JAKs. Indeed, the activating JAK2 V617F mutation, directly linked to deregulated MPL signaling, is present in 50% of PMF patients 7-10 and also induces fibrosis in mice. 11,12 However, how these unique JAK2 or MPL mutations may lead to bone marrow fibrosis development is not yet understood. Notably, both mutations can be found in essential thrombocythemia, 6-10 a myeloproliferative disorder without fibrosis. Thus, PMF is related to TPO/MPL pathway alterations and the TPO high model, mimicking deregulated MPL signaling, appears to be the most relevant to test drugs in vivo.Several lines of evidence obtained from both studies of patients with PMF and of murine models ending with myelofibrosis are in favor of a crucial role (i) of the pleiotropic cytokine transforming growth f...

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Transgenic mice overexpressing murine thrombopoietin develop myelofibrosis and osteosclerosis

Cited by 52 publications

References 32 publications

Osteomyelosclerosis, anemia and extramedullary hematopoiesis in mice lacking the transcription factor NFATc2

Osteomyelosclerosis, anemia and extramedullary hematopoiesis in mice lacking the transcription factor NFATc2

Development of ET, primary myelofibrosis and PV in mice expressing JAK2 V617F

Proteasome inhibitor bortezomib impairs both myelofibrosis and osteosclerosis induced by high thrombopoietin levels in mice

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