Tetraspanin CD9 participates in dysmegakaryopoiesis and stromal interactions in primary myelofibrosis

Primary myelofibrosis is characterized by clonal myeloproliferation, dysmegakaryopoiesis, extramedullary hematopoiesis associated with myelofibrosis and altered stroma in the bone marrow and spleen. The expression of CD9, a tetraspanin known to participate in megakaryopoiesis, platelet formation, cell migration and interaction with stroma, is deregulated in patients with primary myelofibrosis and is correlated with stage of myelofibrosis. We investigated whether CD9 participates in the dysmegakaryopoiesis observed in patients and whether it is involved in the altered interplay between megakaryocytes and stromal cells. We found that CD9 expression was modulated during megakaryocyte differentiation in primary myelofibrosis and that cell surface CD9 engagement by antibody ligation improved the dysmegakaryopoiesis by restoring the balance of MAPK and PI3K signaling. When co-cultured on bone marrow mesenchymal stromal cells from patients, megakaryocytes from patients with primary myelofibrosis displayed modified behaviors in terms of adhesion, cell survival and proliferation as compared to megakaryocytes from healthy donors. These modifications were reversed after antibody ligation of cell surface CD9, suggesting the participation of CD9 in the abnormal interplay between primary myelofibrosis megakaryocytes and stroma. Furthermore, silencing of CD9 reduced CXCL12 and CXCR4 expression in primary myelofibrosis megakaryocytes as well as their CXCL12-dependent migration. Collectively, our results indicate that CD9 plays a role in the dysmegakaryopoiesis that occurs in primary myelofibrosis and affects interactions between megakaryocytes and bone marrow stromal cells. These results strengthen the “bad seed in bad soil” hypothesis that we have previously proposed, in which alterations of reciprocal interactions between hematopoietic and stromal cells participate in the pathogenesis of primary myelofibrosis

Evolution tectono-sédimentaire de la molasse Miocène du bassin d'avant-pays des Alpes occidentales (Massifs subalpins, Jura méridional, Bas-Dauphiné, la Bresse)

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Evolution tectono-sédimentaire de la molasse Miocène du bassin d'avant-pays des Alpes occidentales (Massifs subalpins, Jura méridional, Bas-Dauphiné, la Bresse)

International audienc

Evolution tectono-sédimentaire de la molasse Miocène du bassin d'avant-pays des Alpes occidentales (Massifs subalpins, Jura méridional, Bas-Dauphiné, la Bresse)

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Westward propagation of thrusts in the external Western Alps (France) reappraised from an updated chronostratigraphy of the Miocene Molasses

International audienceThe fact that the western Alps Miocene foreland basin succession is poorly dated impacts directly our understanding of the deformation kinematics of that part of the external part of the Alpine belt (France). Here we propose a multidisciplinary approach aiming at building a robust tectono-stratigraphic framework of the Miocene deposits at the basin scale (northern subalpine massifs, southern Jura, Royans, Bas-Dauphiné and La Bresse basins). Sr isotopes stratigraphy combined with magnetostratigraphy and biostratigraphy enable sequence stratigraphy subdivisions S1 to S8 between the Upper Aquitanian (-21 Ma) and the Tortonian (-9 Ma) dated with a precision This revised chronostratigraphy was complemented with a structural and tectono-sedimentary study based on new fieldwork data and a reappraisal of regional seismic profiles, allowing to highlight five major faults zones (FZ). It appears that the oriental, median and occidental paleogeographical domains are delineated by FZ1, FZ2 and FZ3, therefore suggesting a strong interplay between tectonics and sedimentation. Evidences of syntectonic deposits and a westward migration of the depocenters impart the following deformation chronology : a Oligocene compressive phase (P1) corresponding to thrusting above FZ1 rooted east (above) Belledonne, which generated reliefs that limited the early Miocene transgression to the east; an Early- to Middle Miocene W-WNW/E-ESE-directed compressive phase (P2) involving the Belledonne massif basal thrust, which between 18.05 +/- 0.15 Ma and 12Ma successively activated the Salève thrust fault, and the FZ2 to FZ5 from east to west. P2 deeply impacted the Miocene palaeogeographical evolution by a rapid westward migration of depocenters in response to the exhumation of piggy-back basins above the growing fault zones; a last Tortonian phase (P3), less well constrained, apparently implied a significant uplift in the subalpine massifs, combined with the activation of the frontal Jura thrust