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Tumorigenic role of Musashi-2 in aggressive mantle cell lymphoma

SOX11 overexpression has been associated with aggressive behavior of mantle cell lymphomas (MCL). SOX11 is overexpressed in embryonic and cancer stem cells (CSC) of some tumors. Although CSC have been isolated from primary MCL, their relationship to SOX11 expression and contribution to MCL pathogene...

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Autores principales: Sureda-Gómez, Marta, Balsas, Patricia, Rodríguez, Marta-Leonor, Nadeu, Ferran, De Bolòs, Anna, Eguileor, Álvaro, Kulis, Marta, Castellano, Giancarlo, López, Cristina, Giné, Eva, Demajo, Santiago, Jares, Pedro, Martín-Subero, José I., Beà, Silvia, Campo, Elias, Amador, Virginia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9898029/
https://www.ncbi.nlm.nih.gov/pubmed/36509891
http://dx.doi.org/10.1038/s41375-022-01776-x
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author Sureda-Gómez, Marta
Balsas, Patricia
Rodríguez, Marta-Leonor
Nadeu, Ferran
De Bolòs, Anna
Eguileor, Álvaro
Kulis, Marta
Castellano, Giancarlo
López, Cristina
Giné, Eva
Demajo, Santiago
Jares, Pedro
Martín-Subero, José I.
Beà, Silvia
Campo, Elias
Amador, Virginia
author_facet Sureda-Gómez, Marta
Balsas, Patricia
Rodríguez, Marta-Leonor
Nadeu, Ferran
De Bolòs, Anna
Eguileor, Álvaro
Kulis, Marta
Castellano, Giancarlo
López, Cristina
Giné, Eva
Demajo, Santiago
Jares, Pedro
Martín-Subero, José I.
Beà, Silvia
Campo, Elias
Amador, Virginia
author_sort Sureda-Gómez, Marta
collection PubMed
description SOX11 overexpression has been associated with aggressive behavior of mantle cell lymphomas (MCL). SOX11 is overexpressed in embryonic and cancer stem cells (CSC) of some tumors. Although CSC have been isolated from primary MCL, their relationship to SOX11 expression and contribution to MCL pathogenesis and clinical evolution remain unknown. Here, we observed enrichment in leukemic and hematopoietic stem cells gene signatures in SOX11+ compared to SOX11– MCL primary cases. Musashi-2 (MSI2) emerged as one of the most significant upregulated stem cell-related genes in SOX11+ MCLs. SOX11 is directly bound to the MSI2 promoter upregulating its expression in vitro. MSI2 intronic enhancers were strongly activated in SOX11+ MCL cell lines and primary cases. MSI2 upregulation was significantly associated with poor overall survival independently of other high-risk features of MCL. MSI2 knockdown decreased the expression of genes related to apoptosis and stem cell features and significantly reduced clonogenic growth, tumor cell survival and chemoresistance in MCL cells. MSI2-knockdown cells had reduced tumorigenic engraftment into mice bone marrow and spleen compared to control cells in xenotransplanted mouse models. Our results suggest that MSI2 might play a key role in sustaining stemness and tumor cell survival, representing a possible novel target for therapeutic interventions in MCL.
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spelling pubmed-98980292023-02-05 Tumorigenic role of Musashi-2 in aggressive mantle cell lymphoma Sureda-Gómez, Marta Balsas, Patricia Rodríguez, Marta-Leonor Nadeu, Ferran De Bolòs, Anna Eguileor, Álvaro Kulis, Marta Castellano, Giancarlo López, Cristina Giné, Eva Demajo, Santiago Jares, Pedro Martín-Subero, José I. Beà, Silvia Campo, Elias Amador, Virginia Leukemia Article SOX11 overexpression has been associated with aggressive behavior of mantle cell lymphomas (MCL). SOX11 is overexpressed in embryonic and cancer stem cells (CSC) of some tumors. Although CSC have been isolated from primary MCL, their relationship to SOX11 expression and contribution to MCL pathogenesis and clinical evolution remain unknown. Here, we observed enrichment in leukemic and hematopoietic stem cells gene signatures in SOX11+ compared to SOX11– MCL primary cases. Musashi-2 (MSI2) emerged as one of the most significant upregulated stem cell-related genes in SOX11+ MCLs. SOX11 is directly bound to the MSI2 promoter upregulating its expression in vitro. MSI2 intronic enhancers were strongly activated in SOX11+ MCL cell lines and primary cases. MSI2 upregulation was significantly associated with poor overall survival independently of other high-risk features of MCL. MSI2 knockdown decreased the expression of genes related to apoptosis and stem cell features and significantly reduced clonogenic growth, tumor cell survival and chemoresistance in MCL cells. MSI2-knockdown cells had reduced tumorigenic engraftment into mice bone marrow and spleen compared to control cells in xenotransplanted mouse models. Our results suggest that MSI2 might play a key role in sustaining stemness and tumor cell survival, representing a possible novel target for therapeutic interventions in MCL. Nature Publishing Group UK 2022-12-12 2023 /pmc/articles/PMC9898029/ /pubmed/36509891 http://dx.doi.org/10.1038/s41375-022-01776-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Sureda-Gómez, Marta
Balsas, Patricia
Rodríguez, Marta-Leonor
Nadeu, Ferran
De Bolòs, Anna
Eguileor, Álvaro
Kulis, Marta
Castellano, Giancarlo
López, Cristina
Giné, Eva
Demajo, Santiago
Jares, Pedro
Martín-Subero, José I.
Beà, Silvia
Campo, Elias
Amador, Virginia
Tumorigenic role of Musashi-2 in aggressive mantle cell lymphoma
title Tumorigenic role of Musashi-2 in aggressive mantle cell lymphoma
title_full Tumorigenic role of Musashi-2 in aggressive mantle cell lymphoma
title_fullStr Tumorigenic role of Musashi-2 in aggressive mantle cell lymphoma
title_full_unstemmed Tumorigenic role of Musashi-2 in aggressive mantle cell lymphoma
title_short Tumorigenic role of Musashi-2 in aggressive mantle cell lymphoma
title_sort tumorigenic role of musashi-2 in aggressive mantle cell lymphoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9898029/
https://www.ncbi.nlm.nih.gov/pubmed/36509891
http://dx.doi.org/10.1038/s41375-022-01776-x
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