Tetraspanin CD9 participates in dysmegakaryopoiesis and stromal interactions in primary myelofibrosis

Desterke, Christophe; Martinaud, Christophe; Guerton, Bernadette; Pieri, Lisa; Bogani, Costanza; Clay, Denis; Torossian, Frédéric; Lataillade, Jean‐Jacques; Hasselbach, Hans C.; Gisslinger, Heinz; Demory, Jean-Loup; Dupriez, Brigitte; Boucheix, Claude; Rubinstein, Eric; Amsellem, Sophie; Vannucchi, Alessandro M.; Bousse‐Kerdilès, Marie‐Caroline Le

doi:10.3324/haematol.2014.118497

Cited by 8 publications

(7 citation statements)

References 44 publications

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“…[12][13][14] Once localized in the proximity of marrow sinusoids, MKs are surrounded by a different environment and can either migrate or extend proplatelets through the endothelial barrier. Previous studies have reported that MKs migrate toward an SDF-1a gradient; however, the intracellular processes that regulate MK migration are not well known 9,11,[15][16][17] and constitute a gap in our knowledge.…”

Section: Introductionmentioning

confidence: 99%

Dynamins 2 and 3 control the migration of human megakaryocytes by regulating CXCR4 surface expression and ITGB1 activity

Suraneni¹,

Corey

Hession

et al. 2018

Blood Advances

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Megakaryocyte (MK) migration from the bone marrow periosteal niche toward the vascular niche is a prerequisite for proplatelet extension and release into the circulation. The mechanism for this highly coordinated process is poorly understood. Here we show that dynasore (DNSR), a small-molecule inhibitor of dynamins (DNMs), or short hairpin RNA knockdown of DNM2 and DNM3 impairs directional migration in a human MK cell line or MKs derived from cultured CD34+ cells. Because cell migration requires actin cytoskeletal rearrangements, we measured actin polymerization and the activity of cytoskeleton regulator RhoA and found them to be decreased after inhibition of DNM2 and DNM3. Because SDF-1α is important for hematopoiesis, we studied the expression of its receptor CXCR4 in DNSR-treated cells. CXCR4 expression on the cell surface was increased, at least partially because of slower endocytosis and internalization after SDF-1α treatment. Combined inhibition of DNM2 and DNM3 or forced expression of dominant-negative Dnm2-K44A or GTPase-defective DNM3 diminished β1 integrin (ITGB1) activity. DNSR-treated MKs showed an abnormally clustered staining pattern of Rab11, a marker of recycling endosomes. This suggests decreased recruitment of the recycling pathway in DNSR-treated cells. Altogether, we show that the GTPase activity of DNMs, which governs endocytosis and regulates cell receptor trafficking, exerts control on MK migration toward SDF-1α gradients, such as those originating from the vascular niche. DNMs play a critical role in MKs by triggering membrane-cytoskeleton rearrangements downstream of CXCR4 and integrins.

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Section: Introductionmentioning

confidence: 99%

Dynamins 2 and 3 control the migration of human megakaryocytes by regulating CXCR4 surface expression and ITGB1 activity

Suraneni¹,

Corey

Hession

et al. 2018

Blood Advances

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“…Furthermore, CD9 and CD151 are engaged in thrombopoiesis, CD9 also affects myelopoiesis and CD151 erythropoiesis. These activities essentially depend on the association with integrins and include the crosstalk with the ECM and mesenchymal stem cells [107–111]. We noted reduced CD62P, TER119 and GR1 expression in Tspan8ko and CD151ko BMC.…”

Section: Discussionmentioning

confidence: 77%

“…Wt-TEX can support this process by CD184 induction, possibly in concert with additional chemokine receptors [115, 116]. A direct contribution to CD184 expression was described for CD9, CD184 upregulation modulating megakaryocyte motility and leukemia dissemination [107, 117]. Furthermore, a CD63 mutant inhibits HIV1 entry by disrupting the trafficking of CD184 to the plasma membrane [118].…”

Section: Discussionmentioning

confidence: 99%

Tspan8 and Tspan8/CD151 knockout mice unravel the contribution of tumor and host exosomes to tumor progression

Zhao

Wang

Hackert

et al. 2018

J Exp Clin Cancer Res

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BackgroundThe tetraspanins Tspan8 and CD151 promote metastasis, exosomes (Exo) being suggested to be important in the crosstalk between tumor and host. The contribution of Tspan8 and CD151 to host versus tumor-derived exosome (TEX) activities being not defined, we approached the questions using 3-methylcholanthrene-induced (MCA) tumors from wt, Tspan8ko, CD151ko and Tspan8/CD151 (db)ko mice, implanted into tetraspanin-competent and deficient hosts.MethodsTumor growth and dissemination, hematopoiesis and angiogenesis were surveyed in wild type (wt), Tspan8ko, CD151ko and dbko mice bearing tetraspanin-competent and -deficient MCA tumors. In vitro studies using tumor cells, bone marrow cells (BMC) and endothelial cells (EC) elaborated the mechanism of serum (s)Exo- and TEX-induced target modulation.ResultsTumors grew in autochthonous and syngeneic hosts differing in Tspan8- and/or CD151-competence. However, Tspan8ko- and/or CD151ko-tumor cell dissemination and settlement in metastatic organs was significantly reduced in the autochthonous host, and less severely in the wt-host. Impaired wt-MCA tumor dissemination in the ko-host confirmed a contribution of host- and tumor-Tspan8/-CD151 to tumor cell dissemination, delivery of sExo and TEX being severely impaired by a Tspan8ko/CD151ko. Coculturing tumor cells, BMC and EC with sExo and TEX revealed minor defects in epithelial mesenchymal transition and apoptosis resistance of ko tumors. Strongly reduced migratory and invasive capacity of Tspan8ko/CD151ko-MCA relies on distorted associations with integrins and CAM and missing Tspan8/CD151-promoted recruitment of proteases. The defects, differing between Tspan8ko- and CD151ko-MCA, were rescued by wt-TEX and, less efficiently Tspan8ko- and CD151ko-TEX. Minor defects in hematopoietic progenitor maturation were based on the missing association of hematopoietic growth factors /− receptors with CD151 and, less pronounced, Tspan8. Rescue of impaired angiogenesis in ko mice by wt-sExo and promotion of angiogenesis by TEX depended on the association of Tspan8 and CD151 with GPCR and RTK in EC and tumor cells.ConclusionsTspan8-/CD151-TEX play central roles in tumor progression. Tspan8-/CD151-sExo and TEX contribute by stimulating angiogenesis. Tspan8 and CD151 fulfill these tasks by associating with function-relevant proteins, the additive impact of Tspan8 and CD151 relying on differences in preferred associations. The distinct Tspan8 and CD151 contributions suggest a blockade of TEX-Tspan8 and -CD151 promising for therapeutic intervention.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0961-6) contains supplementary material, which is available to authorized users.

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“…The signal intensities from single experiment raw data lists are normalized by dividing the intensities values by their median. Normalized data were accessible on public database: (GEO submission number GSE44426 , http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE44426 ), online on Jan. 10, 2015) [1] , [2] .…”

Section: Experimental Design Materials and Methodsmentioning

confidence: 99%

Transcriptome analysis of bone marrow mesenchymal stromal cells from patients with primary myelofibrosis

et al. 2015

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Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm whose severity and treatment complexity are attributed to the presence of bone marrow (BM) fibrosis and alterations of stroma impairing the production of normal blood cells. Despite the recently discovered mutations including the JAK2V617F mutation in about half of patients, the primitive event responsible for the clonal proliferation is still unknown. In the highly inflammatory context of PMF, the presence of fibrosis associated with a neoangiogenesis and an osteosclerosis concomitant to the myeloproliferation and to the increase number of circulating hematopoietic progenitors suggests that the crosstalk between hematopoietic and stromal cells is deregulated in the PMF BM microenvironmental niches. Within these niches, mesenchymal stromal cells (BM-MSC) play a hematopoietic supportive role in the production of growth factors and extracellular matrix which regulate the proliferation, differentiation, adhesion and migration of hematopoietic stem/progenitor cells. A transcriptome analysis of BM-MSC in PMF patients will help to characterize their molecular alterations and to understand their involvement in the hematopoietic stem/progenitor cell deregulation that features PMF.

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Tetraspanin CD9 participates in dysmegakaryopoiesis and stromal interactions in primary myelofibrosis

Abstract: ABSTRACTof CD9 expression which precedes the appearance of GPIIb/IIIa. 16 We have previously demonstrated that CD9 participates in normal megakaryopoiesis and platelet formation through its action on megakaryocyte demarcation membrane separation.

Cited by 8 publications

References 44 publications

Dynamins 2 and 3 control the migration of human megakaryocytes by regulating CXCR4 surface expression and ITGB1 activity

Dynamins 2 and 3 control the migration of human megakaryocytes by regulating CXCR4 surface expression and ITGB1 activity

Tspan8 and Tspan8/CD151 knockout mice unravel the contribution of tumor and host exosomes to tumor progression

Transcriptome analysis of bone marrow mesenchymal stromal cells from patients with primary myelofibrosis

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