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  • 1
    Online Resource
    Online Resource
    Osteogenic Potential of Mesenchymal Stromal Cells Contributes to Primary Myelofibrosis
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 22 ( 2015-11-15), p. 4753-4765
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 22 ( 2015-11-15), p. 4753-4765
    Abstract: Primary myelofibrosis is a myeloproliferative neoplasm that is a precursor to myeloid leukemia. Dysmegakaryopoiesis and extramedullary hematopoiesis characterize primary myelofibrosis, which is also associated with bone marrow stromal alterations marked by fibrosis, neoangiogenesis, and osteomyelosclerosis. In particular, contributions to primary myelofibrosis from mesenchymal stromal cells (MSC) have been suggested by mouse studies, but evidence in humans remains lacking. In this study, we show that bone marrow MSCs from primary myelofibrosis patients exhibit unique molecular and functional abnormalities distinct from other myeloproliferative neoplasms and these abnormalities are maintained stably ex vivo in the absence of leukemic cells. Primary myelofibrosis-MSC overexpressed heparin-binding cytokines, including proinflammatory TGFβ1 and osteogenic BMP-2, as well as glycosaminoglycans such as heparan sulfate and chondroitin sulfate. Transcriptome and functional analyses revealed alterations in MSC differentiation characterized by an increased osteogenic potential and a TGFβ1 signaling signature. Accordingly, phospho-Smad2 levels were intrinsically increased in primary myelofibrosis-MSC along with enhanced expression of the master bone regulator RUNX2, while inhibition of the endogenous TGFβ1 receptor TGFβR1 impaired osteogenic differentiation in these MSCs. Taken together, our results define the source of a critical osteogenic function in primary myelofibrosis that supports its pathophysiology, suggesting that combined targeting of both the hematopoietic and stromal cell compartments in primary myelofibrosis patients may heighten therapeutic efficacy. Cancer Res; 75(22); 4753–65. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-14-3696
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 2
    Online Resource
    Online Resource
    Transcriptome analysis of bone marrow mesenchymal stromal cells from patients with primary myelofibrosis
    Elsevier BV ; 2015
    In:  Genomics Data Vol. 5 ( 2015-09), p. 1-2
    Details
    In: Genomics Data, Elsevier BV, Vol. 5 ( 2015-09), p. 1-2
    Type of Medium: Online Resource
    ISSN: 2213-5960
    URL: Article
    DOI: 10.1016/j.gdata.2015.04.017
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2015
    detail.hit.zdb_id: 2751131-5
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  • 3
    Online Resource
    Online Resource
    Impairment of Myeloid Dendritic Differentiation and Role in the Support of Splenic Dysmegakaryopoiesis in Patients with Primary Myelofibrosis
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 1762-1762
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1762-1762
    Abstract: Abstract 1762 Introduction The primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by myeloproliferation, splenomegaly with hematopoietic metaplasia and dysmegakaryopoieisis. We have previously described an increase in Flt3 ligand (FL) in plasma and spleen of patients with PMF and its role in the dysmegakaryopoiesis (Desterke and al, Cancer Res, 2011). Account the importance of FL in development of splenic myeloid dendritic cells (mDC), we studied the differentiation of mDC in patients and its potential impact on dysmegakaryopoiesis. Patients and Methods The mDCs were obtained from cell culture of blood and spleen mononuclear cells in presence of fetal calf serum (FCS) and bacterial lipolysaccharides (LPS). The megakaryocytes were obtained by culturing CD34+ cells from blood or spleen in specific medium serum free in presence of IL-3, IL-6, IL-11 and Tpo. Gene expression was quantified by microarray and RT-QPCR, protein analysis by immunofluorescence and flow cytometry, and migration experiments were performed in Boyden chamber. Results Transcriptome of circulating CD34+ cells from PMF patients showed an increase in expression of genes encoding for integrin CD11c and also TLR4 and a decrease in the expression of gene encoding TLR9: suggesting the presence of progenitor mDCs in the blood. These results have been confirmed 1/ in cytometry by an increase in the number of CD34+ CD11c+ HLA-Dr+ cells in the blood; 2/ in cell culture by the presence of adherent cell colonies positives for TLR4+ CD11c+ HLA-Dr+ in the blood. The in vitro differentiation of mDC cells and the proportion of mature mDCs HLA-Dr+ CD11c+ cells are decreased in blood of PMF patients. Myeloid nature of circulating DCs was confirmed by the absence expression of the plasmacytoid membrane marker CD123 and by an increased of TLR4 and myeloid PU-1 (myeloid transcription factor) expression in opposite to a decreased of plasmacytoid markers: IL-23, HMGB1 and TLR9. Moreover in PMF patients, circulating adherent mDCs overexpressed CXCL12 chemokine and also FL which have abnormal chemottractant ability with respect to PMF megakaryocytic precursors still expressing flt3 receptor. Finally, in PMF patients, coculture of MK with mDC promotes their survival, differentiation and maturation (MK ploidy and transcriptional program). Primary results confirmed the presence of these mDCs precursors (CD34+ CD11c+ HLA-Dr+) in the spleen of PMF patients which harbored also an extramedullary megakaryopoiesis. These mDCs precursors are absent of the spleen from healthy subjects. Conclusion Our results show an increased presence of mDC progenitor population CD34+ HLA-Dr+ CD11c+ in the blood and the spleen of PMF patients. They also suggest that these cells are involved in migration, survival and differentiation/maturation of megakaryocytes, particulary in the spleen of patients. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.1762.1762
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 4
    Online Resource
    Online Resource
    FLT3-Mediated p38–MAPK Activation Participates in the Control of Megakaryopoiesis in Primary Myelofibrosis
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8 ( 2011-04-15), p. 2901-2915
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8 ( 2011-04-15), p. 2901-2915
    Abstract: Primary myelofibrosis (PMF) is characterized by increased number of hematopoietic progenitors and a dysmegakaryopoiesis which supports the stromal reaction defining this disease. We showed that increased ligand (FL) levels in plasma, hematopoietic progenitors, and stromal cells from PMF patients were associated with upregulation of the cognate Flt3 receptor on megakaryocytic (MK) cells. This connection prompted us to study a functional role for the FL/Flt3 couple in PMF dysmegakaryopoiesis, as a route to reveal insights into pathobiology and therapy in this disease. Analysis of PMF CD34+ and MK cell transcriptomes revealed deregulation of the mitogen-activated protein kinase (MAPK) pathway along with Flt3 expression. In PMF patients, a higher proportion of circulating Flt3+CD34+CD41+ cells exhibited an increased MAPK effector phosphorylation independently of Jak2V617F mutation. Activation of FL/Flt3 axis in PMF MK cell cultures, in response to FL, induced activation of the p38–MAPK cascade, which is known to be involved in inflammation, also increasing expression of its target genes (NFATC4, p53, AP-1, IL-8). Inhibiting Flt3 or MAPK or especially p38 by chemical, antibody, or silencing strategies restored megakaryopoiesis and reduced phosphorylation of Flt3 and p38 pathway effectors, confirming the involvement of Flt3 in PMF dysmegakaryopoiesis via p38 activation. In addition, in contrast to healthy donors, MK cells derived from PMF CD34+ cells exhibited an FL-induced migration that could be reversed by p38 inhibition. Taken together, our results implicate the FL/Flt3 ligand–receptor complex in PMF dysmegakaryopoiesis through persistent p38–MAPK activation, with implications for therapeutic prospects to correct altered megakaryopoiesis in an inflammatory context. Cancer Res; 71(8); 2901–15. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-10-1731
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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    detail.hit.zdb_id: 410466-3
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  • 5
    Online Resource
    Online Resource
    Physiopathologie des néoplasies myéloprolifératives ; quand le microenvironnement s’enflamme !
    Elsevier BV ; 2017
    In:  Revue Francophone des Laboratoires Vol. 2017, No. 492 ( 2017-05), p. 41-50
    Details
    In: Revue Francophone des Laboratoires, Elsevier BV, Vol. 2017, No. 492 ( 2017-05), p. 41-50
    Type of Medium: Online Resource
    ISSN: 1773-035X
    URL: Article
    DOI: 10.1016/S1773-035X(17)30163-6
    Language: French
    Publisher: Elsevier BV
    Publication Date: 2017
    detail.hit.zdb_id: 2222772-6
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  • 6
    Online Resource
    Online Resource
    Pre-hospital management of pediatric polytrauma during modern conflict: experience and limits of the French military health service
    Springer Science and Business Media LLC ; 2019
    In:  European Journal of Trauma and Emergency Surgery Vol. 45, No. 3 ( 2019-6), p. 437-443
    Details
    In: European Journal of Trauma and Emergency Surgery, Springer Science and Business Media LLC, Vol. 45, No. 3 ( 2019-6), p. 437-443
    Type of Medium: Online Resource
    ISSN: 1863-9933 , 1863-9941
    URL: Article
    DOI: 10.1007/s00068-018-0915-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2276432-X
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  • 7
    Online Resource
    Online Resource
    Inflammation as a Keystone of Bone Marrow Stroma Alterations in Primary Myelofibrosis
    Hindawi Limited ; 2015
    In:  Mediators of Inflammation Vol. 2015 ( 2015), p. 1-16
    Details
    In: Mediators of Inflammation, Hindawi Limited, Vol. 2015 ( 2015), p. 1-16
    Abstract: Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm where severity as well as treatment complexity is mainly attributed to a long lasting disease and presence of bone marrow stroma alterations as evidenced by myelofibrosis, neoangiogenesis, and osteosclerosis. While recent understanding of mutations role in hematopoietic cells provides an explanation for pathological myeloproliferation, functional involvement of stromal cells in the disease pathogenesis remains poorly understood. The current dogma is that stromal changes are secondary to the cytokine “storm” produced by the hematopoietic clone cells. However, despite therapies targeting the myeloproliferation-sustaining clones, PMF is still regarded as an incurable disease except for patients, who are successful recipients of allogeneic stem cell transplantation. Although the clinical benefits of these inhibitors have been correlated with a marked reduction in serum proinflammatory cytokines produced by the hematopoietic clones, further demonstrating the importance of inflammation in the pathological process, these treatments do not address the role of the altered bone marrow stroma in the pathological process. In this review, we propose hypotheses suggesting that the stroma is inflammatory-imprinted by clonal hematopoietic cells up to a point where it becomes “independent” of hematopoietic cell stimulation, resulting in an inflammatory vicious circle requiring combined stroma targeted therapies.
    Type of Medium: Online Resource
    ISSN: 0962-9351 , 1466-1861
    URL: Article
    DOI: 10.1155/2015/415024
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2015
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  • 8
    Online Resource
    Online Resource
    Endogenous TGF-beta1 Mediated Osteogenic Impairment of Medullar Mesenchymal Stromal Cells in Primary Myelofibrosis
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 1873-1873
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1873-1873
    Abstract: Primary myelofibrosis (PMF) is myeloproliferative neoplasm characterized by clonal myeloproliferation, dysmegakaryopoiesis, extramedullary hematopoiesis associated with myelofibrosis and altered stroma in bone marrow and spleen. Mesenchymal stromal cells (MSCs) are reported to play a pivotal role in fibrosis and stromal changes are considered as a reactive counterpart of the cytokine production by clonal hematopoietic cells. The present study shows that MSCs from patients demonstrate functional abnormalities that are unexpectedly maintained ex-vivo, in culture. Material and Methods: we studied MSCs and bone marrow sections from PMF patients (n=12) as compared to healthy donors (HDs) (n=6). We tested their proliferation, immunophenotype, hematopoiesis supporting capacities, differentiation abilities, in-vivo osteogenic assays, and performed secretome and transcriptome analysis. Results: We found that PMF-MSCs exhibit similar proliferative capacity and long-term hematopoiesis supporting abilities as compare to healthy donors. They overproduce interleukin 6, VEGF, RANTES, PDGF, BMP-2 and surprisingly TGF-beta1. MSCs from fibrotic PMF patients express high levels of glycosaminoglycans. Adipocytes and chondrocytes differentiation abilities were not different as compared to HDs but PMF-MSCs exhibit an increased in vitro potential. Implementation on scaffold in nude mice confirmed, in vivo, this increased osteogenic potential. We then looked into gene expression and discovered that PMF-MSCs show an original transcriptome signature related to osteogenic lineage and TGF-beta1. Indeed, osteogenic genes such as Runx2, Dlx5, Twist1, Noggin, Sclerostin, GDF5 and Serpine1 are deregulated and suggest a potential osteoprogenitor priming of PMF-MSCs. These molecular results also advocated for a TGF-beta1 impregnation that prompted us to study its impact on PMF-MSCs osteogenic differentiation. First, we then showed that Smad2 is intrinsically over-activated in PMF-MSC and that stimulation by TGF-beta1 is associated with an increase phospho-Smad2 level and an enhancement of bone master gene regulator Runx2 expression. Then, we inhibited TGF-beta1 pathway by by SB-431542 and evidenced a specific behavior of osteogenic MSCs differentiation in patients, suggesting involvement of TGF-beta1 in osteogenic impairment. Conclusion: Altogether, our results identify a signature of PMF-MSCs and suggest that they participate in PMF osteogenic dysregulation independently from in vivo local stimulation by clonal hematopoietic cells Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.1873.1873
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
    Online Resource
    Online Resource
    Accessible Chromatin Landscape Reveals a Proliferative Osteoprogenitor Transcriptional Program in Bone Marrow Mesenchymal Stromal Cells from Patients with Primary Myelofibrosis
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 3135-3135
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3135-3135
    Abstract: Primary myelofibrosis (PMF) is chronic myeloproliferative neoplasm characterized by clonal hematopoietic alterations contributing to myeloproliferation, egress of CD34+ cells from bone marrow to spleen associated with extra-medullary hematopoiesis, myelofibrosis with neo-ossification, leading to an osteomyelosclerosis as a result of increased CD146+ osteoprogenitor compartment. Recent studies from our laboratory have reported that bone marrow (BM) mesenchymal stromal cells (MSCs) from PMF patients (PMF-MSCs) showed a transcriptome and functional profile in agreement with an imprinted alteration of their osteogenic potential1 & 2. We performed advanced in silico analysis of accessible chromatin landscape of proliferative hFOB cells (human Fetal OsteoBlastic cell line) and identified 1183 target promoters during early phase of osteoblastic differentiation. Integration of these osteoblastic promoters in the transcriptome of PMF versus healthy donors (HD) BM-MSCs2 revealed an overexpression of 222 genes in the mesenchymal transcriptional program of patients (False discovery rate: FDR 〈 5%), corresponding to a genomic enrichment of 5.95 (Fisher Exact test: p-value 〈 2.2E-16) of the osteoblastic program in PMF-MSC transcriptome. Unsupervised principal component analysis significantly discriminated PMF patients from HD samples (p-value=7.92E-6). Actually, the osteoblastic transcriptional program activated in BM-MSCs from PMF patients shows an enrichment of genes coding for cell functions such as mRNA processing (-log p-value=11.39), MAPK pathway (-log p-value=6.39) and transcription start sites (TSS) bound by the ETS-domain transcription factor ELK1 (-log10 p-value=8.99). Geneset enrichment analysis (GSEA) also reveals an increase of MYC targets in the PMF-MSC transcriptome which shared 11 targets with ELK1 (NES=2.69, p-value 〈 0.001). Interestingly, ELK1-ETS transcription factor downstream of Erk-MAPK is increased in PMF-MSC transcriptome (p-value = 0.0017) and is a target of MYC. These results suggest that the osteoblastic program is over expressed in PMF BM-MSCs and that it is likely controlled by MAPK and MYC. We also showed that a majority of transcription factors link to osteoblastic differentiation such as JUN, NFATC1, SP7, DLX5, FOS, RUNX2 were down regulated in PMF-MSC transcriptome (GSEA NES=-2.79, p-value 〈 0.001), suggesting an imbalance in the proliferative vs. differentiation transcription program in these cells. Erk1/Erk2 was found to be hyperphosphorylated in PMF-MSCs by flow cytometry. Inhibition of the MAPK pathway by PD98059 during the early phase of in vitro MSC osteoblastic differentiation reveals an increase expression of collagen, a marker of differentiation, as shown by confocal microscopy. This is less the case with myc-inhibitor I (Calbiochem), suggesting the participation of the MAPK pathway in the proliferative vs. differentiation balance of MSCs/osteoprogenitors. In conclusion, integration of the open chromatin genomic landscape of the hFOB osteoblast fetal cells in the PMF BM-MSC transcriptome reveals a proliferative program of MSCs/osteoprogenitors associated in vitro with a repression of the differentiation in accordance with an increase proliferative osteoprogenitor priming of PMF-MSCs1 and with the presence of large size osteoblastic cells in vicinity of the neo-ossification area observed in the BM of PMF patients with osteomyelosclerosis.Martinaud C et al., Cancer Res. 2015 Nov 15;75(22):4753-65Martinaud C et al., Genom Data. 2015 Sep; 5: 1-2 Disclosures Vannucchi: Novartis: Honoraria, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.3135.3135
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
    Online Resource
    Online Resource
    The Tetraspanin CD9 Is Involved in Primary Myelofibrosis Dysmegakaryopoiesis Through c-Myb Regulation and Stroma Interactions,
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3834-3834
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3834-3834
    Abstract: Abstract 3834 Introduction: CD9, a four transmembrane glycoprotein belonging to the tetraspanin family, is suggested to regulate cell motility and adhesion and to play a role in megakaryopoiesis. It has been reported to be a molecular marker of primary myelofibrosis (PMF) being characterized by myeloproliferation, dysmegakaryopoiesis, alterated bone marrow/spleen stroma and extramedullary haematopoiesis. CD9 mRNA has been shown to be overexpressed in CD34+ PMF HPs and its membrane expression level was correlated with platelet counts. Our recent data evidencing an alteration of CD9 expression in PMF megakaryocytes (MK) have encouraged us to investigate whether CD9 participates in the dysmegakaryopoiesis and whether it is involved in the dialogue between MK and stromal cells in PMF patients. Patients and Methods: CD34+ cells were MACS selected from the peripheral blood of PMF patients (n=67) and of unmobilized healthy donors (n=61). Functional studies were performed on MK precursor-derived from CD34+ cells cultured in MK medium with ou without monoclonal antibodies (Syb mAb) or siRNAs targeting CD9. CXCL12-induced MK migration was performed in Boyden chambers. Bone marrow mesenchymal stromal cells (MSC) from healthy donors and PMF patients were cultured in DMEM+10%FCS. Results: Our results showed that CD9 membrane expression was altered on CD34+ cells and on MK precursor-derived from PMF CD34+ cells. Binding of CD9 with Syb mAb restored the in vitro megakaryocyte differentiation process that was altered in patients as shown by an increase in: i) megakaryocytic colony formation in semisolid medium, ii) CD41 and CD62p MK differentiation marker and GATA-1 expression, iii) MK cytoplasmic maturation, iv) apoptotic MK number (reduced AKT phosphorylation and Bcl-XL expression and increased percentage of Annexin+ cells). Activation of CD9 was also associated with regulation of MAPK and AKT-GSK3β pathways whose balance is involved in MK differentiation. Treatment of PMF MK precursors by Syb modulated activation of the MAPK pathway as shown by an increased of p38, JNK and GSK3β phosphorylation and of AP-1 mRNA expression. Taking into account the structure of the tetraspanin molecular network, binding with Syb mAb might also impact the effects associated to the multimolecular complex in which CD9 is involved. This prompted us to study the effects of a molecular silencing of CD9 on the PMF MK differentiation. We showed that, in contrast to the Syb mAb, addition of CD9 siRNA to PMF megakaryocytes reduced their transcriptional program including c-Myb, a transcription factor that is involved in CD9 regulation during megakaryopoiesis. Given the role of CD9 in cell migration, we further investigated whether it could be involved in the megakaryocytic precursor migration observed in patients. We showed that silencing CD9 reduced the CXCL12-dependent megakaryocytic precursor migration as well as the CXCR4 and CXCL12 transcription and that this migration involved actin polymerization. c-Myb siRNA restored CXCR4 and CXCL12 expression and reduced actin polymerization suggesting that CD9 was involved, via c-Myb, in the CXCL12-dependent megakaryocytic precursor migration. Effect of CD9 on cell migration is often interpreted as related to modulation of integrins participating in the integrin/tetraspanin network and of their interaction with mesenchymal stromal cells (MSC). We showed that several genes involving the CD9 partner interactome were over-expressed in MSC from PMF bone marrow as compared to MSC from healthy donors. Preliminary results showing that PMF MK precursors display different behaviour in terms of cell survival and adhesion when co-cultured on bone marrow MSC from PMF patients as compared to healthy donors suggest that interactions between MKs and bone marrow MSC is involved in PMF dysmegakaryopoiesis. Addition of Syb reverses these alterations suggesting the participation of CD9 in the abnormal dialogue between MK and MSC. Conclusion: Our results show a deregulation of CD9 expression in megakaryocytes from PMF patients. They also suggest that CD9 i) participates in PMF dysmegakaryopoieis in terms of MK differentiation and survival and ii) is involved in the increased MK precursor migration through alterations of the CXCL12/CXCR4 axis. Our data further support the role of bone marrow stroma in PMF dysmegakaryopoeisis through CD9 interactions. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.3834.3834
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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