Valencia, A. (Ana)

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2010 - 20113

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    Epigenetic regulation of the non-canonical Wnt pathway in acute myeloid leukemia
    (Wiley-Blackwell, 2010) Vilas, A. (Amaia); Cervera, J. (Jose); Roman-Gomez, J. (José); San-Jose-Eneriz, E. (Edurne); Martin, V. (Vanesa); Valencia, A. (Ana); Rodriguez-Otero, P. (Paula); Sanz, M.A. (Miguel A.); Prosper-Cardoso, F. (Felipe); Torres, A. (Antonio); Aguirre-Ena, X. (Xabier); Herrera, C. (Concepción)
    Wnt5a is a member of the Wnt family of proteins that signals through the non-canonical Wnt ⁄ Ca2+pathway to suppress cyclin D1. Deregulation of this pathway has been found in animal models suggesting that it acts as tumour suppressor in acute myeloid leukemia (AML). Although DNA methylation is the main mechanism of regulation of the canonical Wnt pathway in AML, the role of WNT5A abnormalities has never been evaluated in this clinical setting. The methylation status of WNT5A promoter–exon 1 was analyzed by methylation-specific PCR and sequencing in eleven AML-derived cell lines and 252 AML patients. We observed WNT5A hypermethylation in seven cell lines and in 43% (107 ⁄ 252) of AML patients. WNT5A methylation was associated with decreased WNT5A expression (P < 0.001) that was restored after exposure to 5-Aza-2’-deoxycytidine. Moreover, WNT5A hypermethylation correlated with upregulation of CYCLIN D1 expression (P < 0.001). Relapse (15% vs 37%, P < 0.001) and mortality (61% vs 79%, P = 0.004) rates were lower for patients in the non-methylated group. Disease-free survival and overall survival at 6 and 7 years, respectively, were 60% and 27% for unmethylated patients and 20% and 0% for hypermethylated patients (P = 0.0001 and P = 0.04, respectively). Interestingly, significant differences were also observed when the analysis was carried out according to cytogenetic risk groups. We demonstrate that WNT5A, a putative tumor suppressor gene in AML, is silenced by methylation in this disease and that this epigenetic event is associated with upregulation of CYCLIN D1 expression and confers poor prognosis in patients with AML.
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    DNA Methylation Profiles and Their Relationship with Cytogenetic Status in Adult Acute Myeloid Leukemia
    (Public Library of Science, 2010) Fernandez, A. (Agustín); Cervera, J. (Jose); Cigudosa, J.C. (Juan Cruz); Acquadro, F. (Francesco); Roman-Gomez, J. (José); Wunderlich, M. (Mark); Alvarez, S. (Sara); Mulloy, J.C. (James C.); Rodriguez-Perales, S. (Sandra); Valencia, A. (Ana); Siebert, R. (Reiner); Sanz, M.A. (Miguel A.); Esteller, M. (Manel); Maiques, A. (Alba); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Aguirre-Ena, X. (Xabier); Martin-Subero, J.I. (Jose Ignacio); Suela, J. (Javier)
    Background: Aberrant promoter DNA methylation has been shown to play a role in acute myeloid leukemia (AML) pathophysiology. However, further studies to discuss the prognostic value and the relationship of the epigenetic signatures with defined genomic rearrangements in acute myeloid leukemia are required. Methodology/Principal Findings: We carried out high-throughput methylation profiling on 116 de novo AML cases and we validated the significant biomarkers in an independent cohort of 244 AML cases. Methylation signatures were associated with the presence of a specific cytogenetic status. In normal karyotype cases, aberrant methylation of the promoter of DBC1 was validated as a predictor of the disease-free and overall survival. Furthermore, DBC1 expression was significantly silenced in the aberrantly methylated samples. Patients with chromosome rearrangements showed distinct methylation signatures. To establish the role of fusion proteins in the epigenetic profiles, 20 additional samples of human hematopoietic stem/ progenitor cells (HSPC) transduced with common fusion genes were studied and compared with patient samples carrying the same rearrangements. The presence of MLL rearrangements in HSPC induced the methylation profile observed in the MLL-positive primary samples. In contrast, fusion genes such as AML1/ETO or CBFB/MYH11 failed to reproduce the epigenetic signature observed in the patients. Conclusions/Significance: Our study provides a comprehensive epigenetic profiling of AML, identifies new clinical markers for cases with a normal karyotype, and reveals relevant biological information related to the role of fusion proteins on the methylation signature
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    Down-regulation of EVI1 is associated with epigenetic alterations and good prognosis in patients with acute myeloid leukemia
    (Ferrata Storti Foundation, 2011) Sierra, J. (Jorge); Cervera, J. (Jose); Marin-Bejar, O. (Oskar); Valencia, A. (Ana); Sanz, M.A. (Miguel A.); Lahortiga, I. (Idoya); Marcotegui, N. (Nerea); Gomez-Casares, M.T. (María T.); Gomez-Benito, M. (María); Vazquez, I. (Iria); Hernandez-Rivas, J.M. (Jesús M.); Lumbreras, E. (Eva); Brunet, S. (Salut); Carranza, C. (Claudia); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Odero, M.D. (Maria Dolores); Maicas, M. (Miren); Aguirre-Ena, X. (Xabier); Vicente, C. (Carmen)
    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.