Epigenetic activation of SOX11 in lymphoid neoplasms by histone modifications |
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Authors: | Vegliante Maria Carmela Royo Cristina Palomero Jara Salaverria Itziar Balint Balazs Martín-Guerrero Idoia Agirre Xabier Lujambio Amaia Richter Julia Xargay-Torrent Silvia Bea Silvia Hernandez Luis Enjuanes Anna Calasanz María José Rosenwald Andreas Ott German Roman-Gomez José Prosper Felipe Esteller Manel Jares Pedro Siebert Reiner Campo Elias Martín-Subero José I Amador Virginia |
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Affiliation: | Hematopathology Section, Laboratory of Pathology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain. |
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Abstract: | Recent studies have shown aberrant expression of SOX11 in various types of aggressive B-cell neoplasms. To elucidate the molecular mechanisms leading to such deregulation, we performed a comprehensive SOX11 gene expression and epigenetic study in stem cells, normal hematopoietic cells and different lymphoid neoplasms. We observed that SOX11 expression is associated with unmethylated DNA and presence of activating histone marks (H3K9/14Ac and H3K4me3) in embryonic stem cells and some aggressive B-cell neoplasms. In contrast, adult stem cells, normal hematopoietic cells and other lymphoid neoplasms do not express SOX11. Such repression was associated with silencing histone marks H3K9me2 and H3K27me3. The SOX11 promoter of non-malignant cells was consistently unmethylated whereas lymphoid neoplasms with silenced SOX11 tended to acquire DNA hypermethylation. SOX11 silencing in cell lines was reversed by the histone deacetylase inhibitor SAHA but not by the DNA methyltransferase inhibitor AZA. These data indicate that, although DNA hypermethylation of SOX11 is frequent in lymphoid neoplasms, it seems to be functionally inert, as SOX11 is already silenced in the hematopoietic system. In contrast, the pathogenic role of SOX11 is associated with its de novo expression in some aggressive lymphoid malignancies, which is mediated by a shift from inactivating to activating histone modifications. |
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