Publication
Three-way translocation (X;20;16)(p11;q13;q23) in essential thrombocythemia implicates NFATC2 in dysregulation of CSF2 expression and megakaryocyte proliferation
| dc.contributor.author | Vieira, Luís | |
| dc.contributor.author | Vaz, Andreia | |
| dc.contributor.author | Matos, Paulo | |
| dc.contributor.author | Ambrósio, Ana Paula | |
| dc.contributor.author | Nogueira, Manel | |
| dc.contributor.author | Marques, Bárbara | |
| dc.contributor.author | Pereira, AM | |
| dc.contributor.author | Jordan, Peter | |
| dc.contributor.author | da Silva, Maria Gomes | |
| dc.date.accessioned | 2012-10-24T14:53:16Z | |
| dc.date.available | 2012-10-24T14:53:16Z | |
| dc.date.issued | 2012-08 | |
| dc.description.abstract | Essential thrombocythemia (ET) is a myeloproliferative neoplasm essentially characterized by excessive production of platelets. Molecular pathogenesis of ET is linked in approximately half of the patients to intracellular cytokine signaling dysregulation as a result of thrombopoietin receptor or Janus kinase 2 (JAK2) mutations. However, genetic defects underlying cytokine transcription have not been associated with ET. Using molecular cytogenetics and whole-genome array analyses, we uncovered a submicroscopic deletion at 20q13.2 in a JAK2V617F-positive ET patient with an acquired complex chromosome translocation. The deletion encompassed the nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 (NFATC2) gene that encodes a transcription factor involved in the regulation of hematopoietic cytokines. RNA interference-mediated suppression of NFATC2 mRNA or pharmacological inhibition of NFATC2 protein with 11R-VIVIT in cultured JAK2V617F-positive SET-2 megakaryocytes increased colony stimulating factor 2 (granulocyte-macrophage) (CSF2) mRNA and promoted cell proliferation. Moreover, impairment of NFATC2-calcineurin interaction with 11R-VIVIT further reduced the transcription of the NFATC2 gene. Antibody-mediated neutralization of CSF2 cytokine in inhibitor-treated cells prevented 11R-VIVIT-induced cell proliferation, indicating that impairment of NFATC2-calcineurin interaction promotes megakaryocyte proliferation through up-regulation of CSF2 transcription. Our results suggest a model in which haplo-insufficiency of NFATC2 cooperates with activation of the JAK-STAT signaling pathway in the pathogenesis of JAK2V617F-positive ET with del(20q). These results further indicate that pathogenesis of ET may be linked to genetic defects of other transcription factor genes involved in the regulation of cytokine expression. | por |
| dc.identifier.issn | 1045-2257 | |
| dc.identifier.uri | http://hdl.handle.net/10400.18/1029 | |
| dc.language.iso | eng | por |
| dc.peerreviewed | yes | por |
| dc.publisher | Wiley-Blackwell | por |
| dc.relation.publisherversion | http://onlinelibrary.wiley.com/doi/10.1002/gcc.21994/abstract;jsessionid=A3246E0B4AC0F88F5DC8BBA63F49CA6A.d01t01?systemMessage=Wiley+Online+Library+will+be+disrupted+on+27+October+from+10%3A00-12%3A00+BST+%2805%3A00-07%3A00+EDT%29+for+essential+maintenance | por |
| dc.subject | Genómica Funcional e Estrutural | por |
| dc.subject | Thrombocytemia | por |
| dc.subject | Translocation | por |
| dc.subject | NFAT | por |
| dc.title | Three-way translocation (X;20;16)(p11;q13;q23) in essential thrombocythemia implicates NFATC2 in dysregulation of CSF2 expression and megakaryocyte proliferation | por |
| dc.type | journal article | |
| dspace.entity.type | Publication | |
| oaire.citation.endPage | 1108 | por |
| oaire.citation.startPage | 1093 | por |
| oaire.citation.volume | Genes Chromosomes Cancer. 2012 Dec;51(12):1093-1108. doi: 10.1002/gcc.21994. Epub 2012 Aug 22 | por |
| rcaap.rights | restrictedAccess | por |
| rcaap.type | article | por |