Vázquez Urio, Iria

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https://academica-e.unavarra.es/handle/2454/51348

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Vázquez Urio

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Iria

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Ciencias

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0000-0003-0027-6384

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751933

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812309

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2010 - 20122
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Subject: EVI1 ×

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    PublicationOpen Access
    Down-regulation of EVI1 is associated with epigenetic alterations and good prognosis in patients with acute myeloid leukemia
    (Ferrata Storti Foundation, 2012-10-18) Vázquez Urio, Iria; Maicas, Miren; Cervera, José; Agirre, Xabier; Marin-Béjar, Oskar; Marcotegui, Nerea; Vicente, Carmen; Lahortiga, Idoya; Gómez-Benito, María; Carranza, Claudia; Valencia, Ana; Brunet, Salut; Lumbreras, Eva; Prósper, Felipe; Gómez-Casares, Teresa; Hernández-Rivas, Jesús M.; Calasanz, María José; Sanz, Miguel A.; Sierra, Jorge; Odero, María D.; Ciencias; Zientziak; Gobierno de Navarra / Nafarroako Gobernua
    Background The EVI1 gene (3q26) codes for a zinc finger transcription factor with important roles in both mammalian development and leukemogenesis. Over-expression of EVI1 through either 3q26 rearrangements, MLL fusions, or other unknown mechanisms confers a poor prognosis in acute myeloid leukemia. Design and Methods We analyzed the prevalence and prognostic impact of EVI1 over-expression in a series of 476 patients with acute myeloid leukemia, and investigated the epigenetic modifications of the EVI1 locus which could be involved in the transcriptional regulation of this gene. Results Our data provide further evidence that EVI1 over-expression is a poor prognostic marker in acute myeloid leukemia patients less than 65 years old. Moreover, we found that patients with no basal expression of EVI1 had a better prognosis than patients with expression/over-expression (P=0.036). We also showed that cell lines with over-expression of EVI1 had no DNA methylation in the promoter region of the EVI1 locus, and had marks of active histone modifications: H3 and H4 acetylation, and trimethylation of histone H3 lysine 4. Conversely, cell lines with no expression of EVI1 have DNA hypermethylation and are marked by repressive trimethylation of histone H3 lysine 27 at the EVI1 promoter. Conclusions Our results identify EVI1 over-expression as a poor prognostic marker in a large, independent cohort of acute myeloid leukemia patients less than 65 years old, and show that the total absence of EVI1 expression has a prognostic impact on the outcome of such patients. Furthermore, we demonstrated for the first time that an aberrant epigenetic pattern involving DNA methylation, H3 and H4 acetylation, and trimethylation of histone H3 lysine 4 and histone H3 lysine 27 might play a role in the transcriptional regulation of EVI1 in acute myeloid leukemia. This study opens new avenues for a better understanding of the regulation of EVI1 expression at a transcriptional level.
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    PublicationOpen Access
    EVI1 controls proliferation in acute myeloid leukaemia through modulation of miR-1-2
    (Nature Publishing Group, 2010-09-14) Gómez-Benito, María; Conchillo, Ana; García, M. A.; Vázquez Urio, Iria; Maicas, Miren; Vicente, Carmen; Cristobal, I.; Marcotegui, Nerea; García-Ortí, L.; Bandrés Elizalde, Eva; Calasanz, María José ; Alonso, M. M.; Odero, María D.; Ciencias; Zientziak; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua
    Bakground: the EVI1(ecotropic virus integration site 1) gene codes for a zinc-finger transcription factor, whose transcriptional activation leads to a particularly aggressive form of acute myeloid leukaemia (AML). Although, EVI1 interactions with key proteins in hematopoiesis have been previously described, the precise role of this transcription factor in promoting leukaemic transformation is not completely understood. Recent works have identified specific microRNA (miRNA) signatures in different AML subgroups. However, there is no analysis of miRNAs profiles associated with EVI1 overexpression in humans. Methods: we performed QT-RT-PCR to assess the expression of 250 miRNAs in cell lines with or without EVI1 overexpression and in patient samples. We used ChIP assays to evaluated the possible binding of EVI1 binding to the putative miRNA promoter. Proliferation of the different cell lines transfected with the anti- or pre-miRs was quantified by MTT. Results: our data showed that EVI1 expression was significantly correlated with the expression of miR-1-2 and miR-133-a-1 in established cell lines and in patient samples. ChIP assays confirmed that EVI1 binds directly to the promoter of these two miRNAs. However, only miR-1-2 was involved in abnormal proliferation in EVI1 expressing cell lines. Conclusions: our data showed that EVI1 controls proliferation in AML through modulation of miR-1-2. This study contributes to further understand the transcriptional networks involving transcription factors and miRNAs in AML.