Rodriguez-Perales, S. (Sandra)

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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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    Activation of the unfolded protein response (UPR) is associated with cholangiocellular injury, fibrosis and carcinogenesis in an experimental model of fibropolycystic liver disease
    (2022) Latasa, M.U. (María Ujué); Bañares, R. (Rafael); Berasain, C. (Carmen); Arechederra, M. (María); Fernández-Barrena, M.G. (Maite G.); Nevzorova, Y. (Yulia); Peligros, M.I. (María Isabel); Nelson, L.J. (Leonard J.); Avila, M.A. (Matías Antonio); Davis, R.J. (Roger J.); Tortajada, A. (Agustín); Wu, H. (Hanghang); Vidal, A. (August); Rodriguez-Perales, S. (Sandra); Ye, H. (Hui); Reissing, J. (Johanna); Mohamed, M.R. (Mohamed Ramadan); Iraburu-Elizalde, M. (María); Lujambio, A. (Amaya); Martínez-Naves, E. (Eduardo); Trautwein, C. (Christian); Villanueva, A. (Alberto); Vaquero, J. (Javier); Colyn, L. (Leticia); Torres-Ruiz, R. (Raúl); Zheng, K. (Kang); Bruns, T. (Tony); Cubero, F.J. (Francisco Javier); Chen, C. (Chaobo)
    Polycystic liver disease (PLD) is a group of rare disorders that result from structural changes in the biliary tree development in the liver. In the present work, we studied alterations in molecular mechanisms and signaling pathways that might be responsible for these pathologies. We found that activation of the unfolded protein response, a process that occurs in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum, as well as the scarring of the liver tissue, contribute to the pathogenesis of PLD and the development of cancer. As a preclinical animal model we have used mutant mice of a specific signaling pathway, the c-Jun N-terminal kinase 1/2 (Jnk1/2). These mice resemble a perfect model for the study of PLD and early cancer development.