William Vainchenker

..Thus, our data reveal that RGS16 is a negative regulator of CXCR4 signaling in megakaryocytes. We postulate that RGS16 regulation is a mechanism that controls megakaryocyte maturation by regulating signals from the microenvironment...

..Blood. 2001;97:2023-2030)..

..In contrast, loss-of-function mutations of JAK3 and TYK2 lead to immunodeficiency. The role of JAKs as therapeutic targets is starting to expand, as more insights into their structure and activation mechanisms become available...

..Their precise roles in hematopoiesis and in the pathogenesis of MPN, as well as their prognostic impact and potential as a therapeutic target, are currently under investigation...

..Bone marrow -derived cells (BMDCs) can either limit or contribute to the process of pulmonary vascular remodeling. Whether the difference in their effects depends on the mechanism of pulmonary hypertension (PH) remains unknown...

..Finally, the use of a shRNA to decrease MYL9 expression showed that MYL9 was involved in proplatelet formation. MAL/SRF complex is thus involved in platelet formation and megakaryocyte migration by regulating MYL9 and MMP9...

..Similar defects were found in liver cells from TGF-beta1(-/-) embryos on day 14 after vaginal plug. These data indicate that TGF-beta1 is a critical regulator for in vivo homeostasis of the HSCs, especially for their homing potential...

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..Our results demonstrate for the first time that Lyl-1 functions are important for HSC properties and B-cell differentiation and that they are largely distinct from scl functions...

..Our data thus indicate that mutations in the CSF3R gene can be responsible for hereditary neutrophilia mimicking a myeloproliferative disorder...

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..Since the anti-FLAG antibodies do not react with the TPO binding site of the receptor, we hypothesize that they can trigger a distinct signal by dimerizing Mpl in a manner different from that induced by TPO...

..In conclusion, constitutive heterozygous expression of JAK2(V617F) in mice is not embryo-lethal but results in severe PV-like disease with secondary myelofibrosis and not in ET-like disease as expected from patient study...

..Altogether, these results suggest that part of solD4 activity did not rely upon canonical Notch pathway...

..Together, the data strongly suggest that impaired retention may, at least in short-term hematopoietic reconstitution, lead to a diminution in the number of available progenitors required for radioprotection...

..This study demonstrates that the NO pathway can modulate CXCR4 expression in human CD34(+) cells and suggests that NO may play a critical role in the trafficking of hematopoietic progenitors...

..Questions remain regarding the exact contribution of JAK2(V617F) in other myeloproliferative disorders...

..In addition, they suggest a novel explanation for some of the platelet abnormalities characteristic of patients with WAS...

..Taken together, our results suggest that MLC2 phosphorylation is regulated by both ROCK and MLC kinase and plays an important role in platelet biogenesis by controlling PPF and fragmentation...

..This strongly suggests that patient cytokine levels in current JAK2 inhibitor clinical trials modulate the outcome of these therapies...

..Our results suggest that the late failure of cytokinesis responsible for the endomitotic process is related to a partial defect in the Rho/Rock pathway activation...

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..Deletion of the SNAG repressor domain abolished Gfi-1B-induced erythroid maturation, strongly suggesting that Gfi-1B acts in the late stage of erythroid differentiation as a transcriptional repressor...

..However, OPG expression and regulation in primary hematopoietic cells have not been fully investigated...

..Together, these results suggest that MK polyploidization per se does not regulate gene expression but is intrinsically included in the differentiation process...

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..These findings suggest that osteosclerosis in mice with TPO overexpression occurs predominantly via an up-regulation of OPG in host stromal cells leading to disruption of osteoclastogenesis...

..In contrast, erythroid progenitors remained EPO dependent. These results demonstrate that in PMF, the MPL W515L or K mutation induces a spontaneous megakaryocyte (MK) differentiation and occurs in a multipotent HSCs...

..Trophic and immunosuppressive functions of M2-polarized macrophages link fetus and tumor development, and hESCs offer a valuable experimental model for in vitro studies of mechanisms sustaining these processes...

..Finally, bortezomib dramatically improved TPO(high) mouse survival (89% vs 8% at week 52). We conclude that bortezomib appears as a promising therapy for future treatment of PMF patients...

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..These experiments provide new insights into the pathogenesis of JAK2V617F MPD and demonstrate that a JAK2 inhibitor needs to target the HSC compartment for optimal disease control in classical MPD...

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..Because LYL-1 is expressed in erythroid cell populations, we addressed its role in erythropoiesis using knockin mice...

..However, lethality of TPO overexpression was not decreased after treatment, indicating that in this mice model, myeloproliferation rather than fibrosis was probably responsible for the lethality induced by the disorder...

..Collectively, these data indicate that p210(BCR-ABL) could affect CXCR4 by more than one mechanism and suggest that down-regulation of CXCR4 may have important implications in chronic myelogenous leukemia pathogenesis...

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..As this mutation is also found in other myeloproliferative disorders, this unique mutation will permit a new molecular classification of these disorders and novel therapeutical approaches...

..We propose MYH10 detection as a new and simple tool to identify inherited platelet disorders and myeloid neoplasms with abnormalities in RUNX1 and its associated proteins...

..Together, these results demonstrate that the defects in megakaryopoiesis observed in FPD/AML are, in part, related to a deregulation of myosin IIA and IIB expression leading to both a defect in ploidization and proplatelet formation...

..We propose that the down-regulation of NR4A3 in RUNX1-mutated hematopoietic progenitors leads to an increase in the pool of cells susceptible to be hit by secondary leukemic genetic events...

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..Thus, the BCR-ABL embryonic stem cell model that we developed as well as the results obtained in human CML samples suggests a role for STAT3 in the pathogenesis of human CML...

..This indicates that Aurora B is dispensable for MK polyploidization but is necessary to achieve a normal endomitotic process...

..They also suggest that FKBP51 overexpression could be involved in STAT5 activation in IMF cells and in subsequent abnormal growth...

..This novel MEP differentiation system may allow an in-depth exploration of the molecular bases of erythroid and MK commitment and differentiation...

..The myelodysplastic syndromes and myeloproliferative disorders are associated with deregulated production of myeloid cells. The mechanisms underlying these disorders are not well defined...

..This blockade was accompanied by a modulation of the transcriptional program of megakaryocytic differentiation. All these results indicate that Dll4/Notch signaling inhibits human terminal MK differentiation...

..Our results indicate that TET2 disruption affects 5-hmC levels in human myeloid cells and participates in the pathogenesis of myeloid malignancies through the disturbance of myeloid differentiation...

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..Moreover, AML-1 inhibition led to the p19(INK4D) down-regulation in human MKs. These results may explain the molecular link at the transcriptional level between the arrest of endomitosis and the acceleration of MK differentiation...

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..Targeting JAK, MEK and STAT3 pathways could therefore be of therapeutic value, especially in advanced stage CML...

..They also suggest that FKBP51's overexpression in IMF cells could play an important role in the pathogenesis of this myeloproliferative disorder...

..These data provide evidence that TGF-beta1 produced by hematopoietic cells is pivotal for the pathogenesis of myelofibrosis that develops in mice with TPO overexpression...

..Furthermore, chromatin immunoprecipitation experiment demonstrated that Stat3 is recruited to the promoter of aes1 in ES cells. These data demonstrated that the aes1 gene is a direct transcriptional target of Stat3 in ES cells...

..These results demonstrate that Oct4 acts as a master regulator of ESC differentiation...

..Tetraploid cells were also more resistant against UVC and gamma-irradiation. These data indicate the existence of p53-dependent alterations in apoptosis regulation in tetraploid cells...

..Thus, RUNX1-mediated silencing of MYH10 is required for the switch from mitosis to endomitosis, linking polyploidization with megakaryocyte differentiation...

..Our study might provide some keys to understand how a single mutation can give rise to different pathologies...

..Thus, localized caspase activation is causal to proplatelet formation. We conclude that proplatelet formation is regulated by a caspase activation limited to only some cellular compartments...

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..Altogether, our results demonstrate that Srf is an essential regulator of stem cells and MPP adhesion, and suggest that Srf acts mainly through cell-matrix interactions and integrin signaling...

..These findings indicate that the mTOR pathway plays an important role during megakaryopoiesis by regulating ploidy, cell size, and maturation, in part by regulating p21 and cyclin D3...

..Our findings delineate a molecular pathway through which DNA damage, failure to arrest the cell cycle and inhibition of apoptosis can favor the occurrence of cytogenetic abnormalities that are likely to participate in oncogenesis...

..Thus, proplatelet formation in human MKs could be tightly regulated by differential interactions with their collagen receptors. We propose that this interaction with collagen prevents proplatelet formation within the marrow...