Pivotal contributions of megakaryocytes to the biology of idiopathic myelofibrosis

Ciurea, Stefan O.; Merchant, Delwin; Mahmud, Nadim; Ishii, Takefumi; Zhao, Yan; Hu, Wen‐Yang; Bruno, Edward; Barosi, Giovanni; Xu, Mingjiang; Hoffman, Ronald

doi:10.1182/blood-2006-12-064626

Cited by 185 publications

(192 citation statements)

References 41 publications

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“…Megakaryocytes from Gata1 low mice and from PMF patients express, however, the same intrinsic abnormalities (i.e. higher frequency and higher retention in the marrow because of maturation retardation [6][7][8]56 and increased localization near the endosteum, in close spatial relationship with the osteoblasts 57 . All these factors can contribute to the increased megakaryocyte up-take of SDF-1.…”

Section: Discussionmentioning

confidence: 99%

Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

Migliaccio

Martelli

Verrucci

et al. 2008

Experimental Hematology

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Objective-To assess whether alterations in the SDF-1/CXCR4 occur in patients with primary myelofibrosis (PMF) and in Gata1 low mice, an animal model for myelofibrosis, and whether these abnormalities might account for increased stem/progenitor cell trafficking.Materials and Methods-In the mouse, SDF-1 mRNA levels were assayed in liver, spleen and marrow. SDF-1 protein levels were quantified in plasma and marrow and CXCR4 mRNA and protein levels were evaluated on stem/progenitor cells and megakaryocytes purified from the marrow. SDF-1 protein levels were also evaluated in plasma and in marrow biopsy specimens obtained from normal donors and PMF patients.Results-In Gata1 low mice, the plasma SDF-1 protein was 5-times higher than normal in younger animals. Furthermore, SDF-1 immuno-staining of marrow sections progressively increased with age. Similar abnormalities were observed in PMF patients. In fact, the plasma SDF-1 levels in PMF patients were significantly higher (by 2-fold) than normal (p<0.01) and SDF-1 immuno-staining of marrow biopsiy specimens demonstrated increased SDF-1 deposition in specific areas. In two of the patients, SDF-1 deposition was normalized by curative therapy with allogenic stem cell transplantation. Similarly to what already has been reported for PMF patients, the marrow from Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Gata1 low mice contained fewer CXCR4 pos CD117 pos cells and these cells expressed low levels of CXCR4 mRNA and protein. NIH Public AccessConclusion-Similar abnormalities in the SDF-1/CXCR4 axis are observed in PMF patients and in the Gata1 low mice model of myelofibrosis. We suggest that these abnormalities contribute to the increased stem/progenitor cell trafficking observed in this mouse model as well as patients with PMF.

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Section: Discussionmentioning

confidence: 99%

Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

Migliaccio

Martelli

Verrucci

et al. 2008

Experimental Hematology

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“…3D). Expression of AGGF1 in human megakaryocytes is a novel finding, adding this angiogenic mediator to many others expressed in platelets and progenitors [18][19][20].…”

Section: Growth Factors In Megakaryocytesmentioning

confidence: 99%

X‐linked thrombocytopenia with thalassemia displays bone marrow reticulin fibrosis and enhanced angiogenesis: Comparisons with primary myelofibrosis

et al. 2015

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X‐linked thrombocytopenia with thalassemia (XLTT) is caused by the mutation 216R > Q in exon 4 of the GATA1 gene. Male hemizygous patients display macrothrombocytopenia, splenomegaly, and a β‐thalassemia trait. We describe two XLTT families where three males were initially misdiagnosed as having primary myelofibrosis (PMF) and all five investigated males showed mild‐moderate bone marrow (BM) reticulin fibrosis. Comparative investigations were performed on blood samples and BM biopsies from males with XLTT, PMF patients and healthy controls. Like PMF, XLTT presented with high BM microvessel density, low GATA1 protein levels in megakaryocytes, and elevated blood CD34+ cell counts. But unlike PMF, the BM microvessel pericyte coverage was low in XLTT, and no collagen fibrosis was found. Further, as evaluated by immunohistochemistry, expressions of the growth factors VEGF, AGGF1, and CTGF were low in XLTT megakaryocytes and microvessels but high in PMF. Thus, although the reticulin fibrosis in XLTT might simulate PMF, opposing stromal and megakaryocyte features may facilitate differential diagnosis. Additional comparisons between these disorders may increase the understanding of mechanisms behind BM fibrosis in relation to pathological megakaryopoiesis. Am. J. Hematol. 90:E44–E48, 2015. © 2014 Wiley Periodicals, Inc.

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“…1 Megakaryocytes are 'filled' with different fibrogenic factors, among which transforming growth factor beta1 (TGFb1) mostly contributes to BM fibrosis associated with BM disorders, such as hairy cell leukemia and myelofibrosis. 2,3 Besides its fibrogenic activity, TGFb is a pleiotropic regulator of all stages of hematopoiesis the activity of which depends on the differentiation stage of the target cell, the local environment and the concentration. 4,5 However, the role of TGFb1 on megakaryocyte proliferation, differentiation and proplatelet formation has been poorly investigated.…”

Section: Introductionmentioning

confidence: 99%

Involvement of TGF 1 in autocrine regulation of proplatelet formation in healthy subjects and patients with primary myelofibrosis

et al. 2013

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Pivotal contributions of megakaryocytes to the biology of idiopathic myelofibrosis

Cited by 185 publications

References 41 publications

Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

X‐linked thrombocytopenia with thalassemia displays bone marrow reticulin fibrosis and enhanced angiogenesis: Comparisons with primary myelofibrosis

Involvement of TGF 1 in autocrine regulation of proplatelet formation in healthy subjects and patients with primary myelofibrosis

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