A pathobiologic pathway linking thrombopoietin, GATA-1, and TGF-β1 in the development of myelofibrosis

Vannucchi, Alessandro M.; Bianchi, Lucia; Paoletti, Francesco; Pancrazzi, Alessandro; Torre, Eugenio; Nishikawa, Mitsuo; Zingariello, Maria; Baldassarre, Angela Di; Rana, Rosa Alba; Lorenzini, R; Alfani, Elena; Migliaccio, Giovanni; Migliaccio, Anna Rita

doi:10.1182/blood-2004-04-1320

Cited by 103 publications

(106 citation statements)

References 36 publications

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“…The expression of CXCR4 on the surface of the circulating CD117 pos cells was analyzed as well. As previously described 12 , the blood from Gata1 low mice contains greater numbers of progenitor cells than the blood from wild type littermates (Table 1 and Figure 4B). The contour plots of the CXCR4 staining of the CD117 pos cells in the blood and in the marrow of Gata1 low mice were identical ( Figure 4B).…”

Section: Stem/progenitor Cells From the Marrow And The Blood Of Gata1supporting

confidence: 73%

“…Alternatively, anatomical abnormalities may not be sufficient to alter the balance of events that result in the retention of stem/progenitor cells within the marrow. Other parameters, such as changes in chemokine levels 10,[12][13][14] and/or disruption of adhesive interactions favoring retention of stem/progenitor cells within the marrow 15 , may be operational.…”

Section: Introductionmentioning

confidence: 99%

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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: Stem/progenitor Cells From the Marrow And The Blood Of Gata1supporting

confidence: 73%

Section: Introductionmentioning

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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“…These include TGF-b, mainly TGF-b1, basic fibroblast growth factor and platelet-derived growth factor. [105][106][107][108] Some of the strongest evidence for a prominent role of TGF-b in the generation of myelofibrosis involved the use of BM cells from Tgf-b1 null mice. To induce myelofibrosis, irradiated mice were transplanted with BM cells transduced with vectors containing the thrombopoietin gene.…”

Section: Spotlightmentioning

confidence: 99%

The role of Smad signaling in hematopoiesis and translational hematology

2011

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Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) of adult individuals and function to produce and regenerate the entire blood and immune system over the course of an individual's lifetime. Historically, HSCs are among the most thoroughly characterized tissue-specific stem cells. Despite this, the regulation of fate options, such as self-renewal and differentiation, has remained elusive, partly because of the expansive plethora of factors and signaling cues that govern HSC behavior in vivo. In the BM, HSCs are housed in specialized niches that dovetail the behavior of HSCs with the need of the organism. The Smad-signaling pathway, which operates downstream of the transforming growth factor-b (TGF-b) superfamily of ligands, regulates a diverse set of biological processes, including proliferation, differentiation and apoptosis, in many different organ systems. Much of the function of Smad signaling in hematopoiesis has remained nebulous due to early embryonic lethality of most knockout mouse models. However, recently new data have been uncovered, suggesting that the Smad-signaling circuitry is intimately linked to HSC regulation. In this review, we bring the Smad-signaling pathway into focus, chronicling key concepts and recent advances with respect to TGF-b-superfamily signaling in normal and leukemic hematopoiesis.

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“…145 A pathway linking Tpo, GATA-1 and TGF-b in the development of myelofibrosis was invoked, given that mice expressing low levels of the transcription factor GATA-1 also develop myelofibrosis. 146 …”

Section: Mpns and Tgf-bmentioning

confidence: 99%

Aberrant signal transduction pathways in myeloproliferative neoplasms

2008

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The BCR-ABL-negative myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), entered the spotlight in 2005 when the unique somatic acquired JAK2 V617F mutation was described in 495% of PV and in 50% of ET and PMF patients. For the very rare PV patients who do not harbor the JAK2 V617F mutation, exon 12 JAK2 mutants were discovered also to result in activated forms of JAK2. A minority of ET and PMF patients harbor mutations that constitutively activate the thrombopoietin receptor (TpoR). In bone marrow reconstitution models based on retroviral transduction, the phenotype induced by JAK2 V617F is less severe and different from the rapid fatal myelofibrosis induced by TpoR W515L. The reasons for these differences are unknown. Exactly by which mechanism(s) one acquired somatic mutation, JAK2 V617F, can promote three different diseases remains a mystery, although gene dosage and host genetic variation might have important functions. We review the recent progress made in deciphering signaling anomalies in PV, ET and PMF, with an emphasis on the relationship between JAK2 V617F and cytokine receptor signaling and on cross-talk with several other signaling pathways.

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A pathobiologic pathway linking thrombopoietin, GATA-1, and TGF-β1 in the development of myelofibrosis

Cited by 103 publications

References 36 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

The role of Smad signaling in hematopoiesis and translational hematology

Aberrant signal transduction pathways in myeloproliferative neoplasms

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