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Impact of supraphysiologic MDM2 expression on chromatin networks and therapeutic responses in sarcoma

Amplification of MDM2 on supernumerary chromosomes is a common mechanism of P53 inactivation across tumors. Here, we investigated the impact of MDM2 overexpression on chromatin, gene expression, and cellular phenotypes in liposarcoma. Three independent regulatory circuits predominate in aggressive,...

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Autores principales: Bevill, Samantha M., Casaní-Galdón, Salvador, El Farran, Chadi A., Cytrynbaum, Eli G., Macias, Kevin A., Oldeman, Sylvie E., Oliveira, Kayla J., Moore, Molly M., Hegazi, Esmat, Adriaens, Carmen, Najm, Fadi J., Demetri, George D., Cohen, Sonia, Mullen, John T., Riggi, Nicolò, Johnstone, Sarah E., Bernstein, Bradley E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10363746/
https://www.ncbi.nlm.nih.gov/pubmed/37492096
http://dx.doi.org/10.1016/j.xgen.2023.100321
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author Bevill, Samantha M.
Casaní-Galdón, Salvador
El Farran, Chadi A.
Cytrynbaum, Eli G.
Macias, Kevin A.
Oldeman, Sylvie E.
Oliveira, Kayla J.
Moore, Molly M.
Hegazi, Esmat
Adriaens, Carmen
Najm, Fadi J.
Demetri, George D.
Cohen, Sonia
Mullen, John T.
Riggi, Nicolò
Johnstone, Sarah E.
Bernstein, Bradley E.
author_facet Bevill, Samantha M.
Casaní-Galdón, Salvador
El Farran, Chadi A.
Cytrynbaum, Eli G.
Macias, Kevin A.
Oldeman, Sylvie E.
Oliveira, Kayla J.
Moore, Molly M.
Hegazi, Esmat
Adriaens, Carmen
Najm, Fadi J.
Demetri, George D.
Cohen, Sonia
Mullen, John T.
Riggi, Nicolò
Johnstone, Sarah E.
Bernstein, Bradley E.
author_sort Bevill, Samantha M.
collection PubMed
description Amplification of MDM2 on supernumerary chromosomes is a common mechanism of P53 inactivation across tumors. Here, we investigated the impact of MDM2 overexpression on chromatin, gene expression, and cellular phenotypes in liposarcoma. Three independent regulatory circuits predominate in aggressive, dedifferentiated tumors. RUNX and AP-1 family transcription factors bind mesenchymal gene enhancers. P53 and MDM2 co-occupy enhancers and promoters associated with P53 signaling. When highly expressed, MDM2 also binds thousands of P53-independent growth and stress response genes, whose promoters engage in multi-way topological interactions. Overexpressed MDM2 concentrates within nuclear foci that co-localize with PML and YY1 and could also contribute to P53-independent phenotypes associated with supraphysiologic MDM2. Importantly, we observe striking cell-to-cell variability in MDM2 copy number and expression in tumors and models. Whereas liposarcoma cells are generally sensitive to MDM2 inhibitors and their combination with pro-apoptotic drugs, MDM2-high cells tolerate them and may underlie the poor clinical efficacy of these agents.
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spelling pubmed-103637462023-07-25 Impact of supraphysiologic MDM2 expression on chromatin networks and therapeutic responses in sarcoma Bevill, Samantha M. Casaní-Galdón, Salvador El Farran, Chadi A. Cytrynbaum, Eli G. Macias, Kevin A. Oldeman, Sylvie E. Oliveira, Kayla J. Moore, Molly M. Hegazi, Esmat Adriaens, Carmen Najm, Fadi J. Demetri, George D. Cohen, Sonia Mullen, John T. Riggi, Nicolò Johnstone, Sarah E. Bernstein, Bradley E. Cell Genom Article Amplification of MDM2 on supernumerary chromosomes is a common mechanism of P53 inactivation across tumors. Here, we investigated the impact of MDM2 overexpression on chromatin, gene expression, and cellular phenotypes in liposarcoma. Three independent regulatory circuits predominate in aggressive, dedifferentiated tumors. RUNX and AP-1 family transcription factors bind mesenchymal gene enhancers. P53 and MDM2 co-occupy enhancers and promoters associated with P53 signaling. When highly expressed, MDM2 also binds thousands of P53-independent growth and stress response genes, whose promoters engage in multi-way topological interactions. Overexpressed MDM2 concentrates within nuclear foci that co-localize with PML and YY1 and could also contribute to P53-independent phenotypes associated with supraphysiologic MDM2. Importantly, we observe striking cell-to-cell variability in MDM2 copy number and expression in tumors and models. Whereas liposarcoma cells are generally sensitive to MDM2 inhibitors and their combination with pro-apoptotic drugs, MDM2-high cells tolerate them and may underlie the poor clinical efficacy of these agents. Elsevier 2023-05-11 /pmc/articles/PMC10363746/ /pubmed/37492096 http://dx.doi.org/10.1016/j.xgen.2023.100321 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Bevill, Samantha M.
Casaní-Galdón, Salvador
El Farran, Chadi A.
Cytrynbaum, Eli G.
Macias, Kevin A.
Oldeman, Sylvie E.
Oliveira, Kayla J.
Moore, Molly M.
Hegazi, Esmat
Adriaens, Carmen
Najm, Fadi J.
Demetri, George D.
Cohen, Sonia
Mullen, John T.
Riggi, Nicolò
Johnstone, Sarah E.
Bernstein, Bradley E.
Impact of supraphysiologic MDM2 expression on chromatin networks and therapeutic responses in sarcoma
title Impact of supraphysiologic MDM2 expression on chromatin networks and therapeutic responses in sarcoma
title_full Impact of supraphysiologic MDM2 expression on chromatin networks and therapeutic responses in sarcoma
title_fullStr Impact of supraphysiologic MDM2 expression on chromatin networks and therapeutic responses in sarcoma
title_full_unstemmed Impact of supraphysiologic MDM2 expression on chromatin networks and therapeutic responses in sarcoma
title_short Impact of supraphysiologic MDM2 expression on chromatin networks and therapeutic responses in sarcoma
title_sort impact of supraphysiologic mdm2 expression on chromatin networks and therapeutic responses in sarcoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10363746/
https://www.ncbi.nlm.nih.gov/pubmed/37492096
http://dx.doi.org/10.1016/j.xgen.2023.100321
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