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Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma

Multiple myeloma (MM) is a plasma cell neoplasm associated with a broad variety of genetic lesions. In spite of this genetic heterogeneity, MMs share a characteristic malignant phenotype whose underlying molecular basis remains poorly characterized. In the present study, we examined plasma cells fro...

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Autores principales: Ordoñez, Raquel, Kulis, Marta, Russiñol, Nuria, Chapaprieta, Vicente, Carrasco-Leon, Arantxa, García-Torre, Beatriz, Charalampopoulou, Stella, Clot, Guillem, Beekman, Renée, Meydan, Cem, Duran-Ferrer, Martí, Verdaguer-Dot, Núria, Vilarrasa-Blasi, Roser, Soler-Vila, Paula, Garate, Leire, Miranda, Estíbaliz, San José-Enériz, Edurne, Rodriguez-Madoz, Juan R., Ezponda, Teresa, Martínez-Turrilas, Rebeca, Vilas-Zornoza, Amaia, Lara-Astiaso, David, Dupéré-Richer, Daphné, Martens, Joost H.A., El-Omri, Halima, Taha, Ruba Y., Calasanz, Maria J., Paiva, Bruno, San Miguel, Jesus, Flicek, Paul, Gut, Ivo, Melnick, Ari, Mitsiades, Constantine S., Licht, Jonathan D., Campo, Elias, Stunnenberg, Hendrik G., Agirre, Xabier, Prosper, Felipe, Martin-Subero, Jose I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545147/
https://www.ncbi.nlm.nih.gov/pubmed/32820006
http://dx.doi.org/10.1101/gr.265520.120
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author Ordoñez, Raquel
Kulis, Marta
Russiñol, Nuria
Chapaprieta, Vicente
Carrasco-Leon, Arantxa
García-Torre, Beatriz
Charalampopoulou, Stella
Clot, Guillem
Beekman, Renée
Meydan, Cem
Duran-Ferrer, Martí
Verdaguer-Dot, Núria
Vilarrasa-Blasi, Roser
Soler-Vila, Paula
Garate, Leire
Miranda, Estíbaliz
San José-Enériz, Edurne
Rodriguez-Madoz, Juan R.
Ezponda, Teresa
Martínez-Turrilas, Rebeca
Vilas-Zornoza, Amaia
Lara-Astiaso, David
Dupéré-Richer, Daphné
Martens, Joost H.A.
El-Omri, Halima
Taha, Ruba Y.
Calasanz, Maria J.
Paiva, Bruno
San Miguel, Jesus
Flicek, Paul
Gut, Ivo
Melnick, Ari
Mitsiades, Constantine S.
Licht, Jonathan D.
Campo, Elias
Stunnenberg, Hendrik G.
Agirre, Xabier
Prosper, Felipe
Martin-Subero, Jose I.
author_facet Ordoñez, Raquel
Kulis, Marta
Russiñol, Nuria
Chapaprieta, Vicente
Carrasco-Leon, Arantxa
García-Torre, Beatriz
Charalampopoulou, Stella
Clot, Guillem
Beekman, Renée
Meydan, Cem
Duran-Ferrer, Martí
Verdaguer-Dot, Núria
Vilarrasa-Blasi, Roser
Soler-Vila, Paula
Garate, Leire
Miranda, Estíbaliz
San José-Enériz, Edurne
Rodriguez-Madoz, Juan R.
Ezponda, Teresa
Martínez-Turrilas, Rebeca
Vilas-Zornoza, Amaia
Lara-Astiaso, David
Dupéré-Richer, Daphné
Martens, Joost H.A.
El-Omri, Halima
Taha, Ruba Y.
Calasanz, Maria J.
Paiva, Bruno
San Miguel, Jesus
Flicek, Paul
Gut, Ivo
Melnick, Ari
Mitsiades, Constantine S.
Licht, Jonathan D.
Campo, Elias
Stunnenberg, Hendrik G.
Agirre, Xabier
Prosper, Felipe
Martin-Subero, Jose I.
author_sort Ordoñez, Raquel
collection PubMed
description Multiple myeloma (MM) is a plasma cell neoplasm associated with a broad variety of genetic lesions. In spite of this genetic heterogeneity, MMs share a characteristic malignant phenotype whose underlying molecular basis remains poorly characterized. In the present study, we examined plasma cells from MM using a multi-epigenomics approach and demonstrated that, when compared to normal B cells, malignant plasma cells showed an extensive activation of regulatory elements, in part affecting coregulated adjacent genes. Among target genes up-regulated by this process, we found members of the NOTCH, NF-kB, MTOR signaling, and TP53 signaling pathways. Other activated genes included sets involved in osteoblast differentiation and response to oxidative stress, all of which have been shown to be associated with the MM phenotype and clinical behavior. We functionally characterized MM-specific active distant enhancers controlling the expression of thioredoxin (TXN), a major regulator of cellular redox status and, in addition, identified PRDM5 as a novel essential gene for MM. Collectively, our data indicate that aberrant chromatin activation is a unifying feature underlying the malignant plasma cell phenotype.
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spelling pubmed-75451472020-10-19 Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma Ordoñez, Raquel Kulis, Marta Russiñol, Nuria Chapaprieta, Vicente Carrasco-Leon, Arantxa García-Torre, Beatriz Charalampopoulou, Stella Clot, Guillem Beekman, Renée Meydan, Cem Duran-Ferrer, Martí Verdaguer-Dot, Núria Vilarrasa-Blasi, Roser Soler-Vila, Paula Garate, Leire Miranda, Estíbaliz San José-Enériz, Edurne Rodriguez-Madoz, Juan R. Ezponda, Teresa Martínez-Turrilas, Rebeca Vilas-Zornoza, Amaia Lara-Astiaso, David Dupéré-Richer, Daphné Martens, Joost H.A. El-Omri, Halima Taha, Ruba Y. Calasanz, Maria J. Paiva, Bruno San Miguel, Jesus Flicek, Paul Gut, Ivo Melnick, Ari Mitsiades, Constantine S. Licht, Jonathan D. Campo, Elias Stunnenberg, Hendrik G. Agirre, Xabier Prosper, Felipe Martin-Subero, Jose I. Genome Res Research Multiple myeloma (MM) is a plasma cell neoplasm associated with a broad variety of genetic lesions. In spite of this genetic heterogeneity, MMs share a characteristic malignant phenotype whose underlying molecular basis remains poorly characterized. In the present study, we examined plasma cells from MM using a multi-epigenomics approach and demonstrated that, when compared to normal B cells, malignant plasma cells showed an extensive activation of regulatory elements, in part affecting coregulated adjacent genes. Among target genes up-regulated by this process, we found members of the NOTCH, NF-kB, MTOR signaling, and TP53 signaling pathways. Other activated genes included sets involved in osteoblast differentiation and response to oxidative stress, all of which have been shown to be associated with the MM phenotype and clinical behavior. We functionally characterized MM-specific active distant enhancers controlling the expression of thioredoxin (TXN), a major regulator of cellular redox status and, in addition, identified PRDM5 as a novel essential gene for MM. Collectively, our data indicate that aberrant chromatin activation is a unifying feature underlying the malignant plasma cell phenotype. Cold Spring Harbor Laboratory Press 2020-09 /pmc/articles/PMC7545147/ /pubmed/32820006 http://dx.doi.org/10.1101/gr.265520.120 Text en © 2020 Ordoñez et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
spellingShingle Research
Ordoñez, Raquel
Kulis, Marta
Russiñol, Nuria
Chapaprieta, Vicente
Carrasco-Leon, Arantxa
García-Torre, Beatriz
Charalampopoulou, Stella
Clot, Guillem
Beekman, Renée
Meydan, Cem
Duran-Ferrer, Martí
Verdaguer-Dot, Núria
Vilarrasa-Blasi, Roser
Soler-Vila, Paula
Garate, Leire
Miranda, Estíbaliz
San José-Enériz, Edurne
Rodriguez-Madoz, Juan R.
Ezponda, Teresa
Martínez-Turrilas, Rebeca
Vilas-Zornoza, Amaia
Lara-Astiaso, David
Dupéré-Richer, Daphné
Martens, Joost H.A.
El-Omri, Halima
Taha, Ruba Y.
Calasanz, Maria J.
Paiva, Bruno
San Miguel, Jesus
Flicek, Paul
Gut, Ivo
Melnick, Ari
Mitsiades, Constantine S.
Licht, Jonathan D.
Campo, Elias
Stunnenberg, Hendrik G.
Agirre, Xabier
Prosper, Felipe
Martin-Subero, Jose I.
Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma
title Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma
title_full Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma
title_fullStr Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma
title_full_unstemmed Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma
title_short Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma
title_sort chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545147/
https://www.ncbi.nlm.nih.gov/pubmed/32820006
http://dx.doi.org/10.1101/gr.265520.120
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