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http://hdl.handle.net/10400.18/1029
Título: | Three-way translocation (X;20;16)(p11;q13;q23) in essential thrombocythemia implicates NFATC2 in dysregulation of CSF2 expression and megakaryocyte proliferation |
Autor: | Vieira, Luís Vaz, Andreia Matos, Paulo Ambrósio, Ana Paula Nogueira, Manel Marques, Bárbara Pereira, AM Jordan, Peter da Silva, Maria Gomes |
Palavras-chave: | Genómica Funcional e Estrutural Thrombocytemia Translocation NFAT |
Data: | Ago-2012 |
Editora: | Wiley-Blackwell |
Resumo: | 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. |
Peer review: | yes |
URI: | http://hdl.handle.net/10400.18/1029 |
ISSN: | 1045-2257 |
Versão do Editor: | 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 |
Aparece nas colecções: | DGH - Artigos em revistas internacionais |
Ficheiros deste registo:
Ficheiro | Descrição | Tamanho | Formato | |
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NFAT paper Luis_GCC12 online.pdf | 688,11 kB | Adobe PDF | Ver/Abrir Acesso Restrito. Solicitar cópia ao autor! |
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