YPEL2 regulates the efficacy of BRD4-EZH2 dual targeting in EZH2Y641mut germinal center-derived lymphoma
A significant proportion of diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) cases harbor a gain-of-function, heterozygous somatic mutation of the methyltransferase gene EZH2. While this factor is known to cooperate with the proto-oncogene MYC during malignant B cell development, t...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-03-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558625000107 |
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| author | Aránzazu Chamorro-Jorganes Núria Profitós-Pelejà Clara Recasens-Zorzo Juan G Valero Diana Reyes-Garau Laura Magnano Ray Butler Antonio Postigo Patricia Pérez-Galán Marcelo Lima Ribeiro Gaël Roué |
| author_facet | Aránzazu Chamorro-Jorganes Núria Profitós-Pelejà Clara Recasens-Zorzo Juan G Valero Diana Reyes-Garau Laura Magnano Ray Butler Antonio Postigo Patricia Pérez-Galán Marcelo Lima Ribeiro Gaël Roué |
| author_sort | Aránzazu Chamorro-Jorganes |
| collection | DOAJ |
| description | A significant proportion of diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) cases harbor a gain-of-function, heterozygous somatic mutation of the methyltransferase gene EZH2. While this factor is known to cooperate with the proto-oncogene MYC during malignant B cell development, the effect of interfering with both factors remains underexplored. Here we undertook the simultaneous evaluation of two epigenetic drugs targeting EZH2 methyltransferase activity and BRD4-mediated control of MYC transcription, CPI169 and CPI203, using preclinical models of DLBCL and FL with distinct EZH2 mutational status. We observed a specific and synergistic antiproliferative effect of these compounds in EZH2-mutated cells and mouse xenograft models, that was related to the abrogation of MYC transcriptional program and to tumor cell proliferation blockade at the G1 cell cycle phase. Gene expression profile, exploratory data analysis, and siRNA screening identified the PI3K/AKT-regulated gene and mitosis regulator, YPEL2, as a crucial factor involved in the efficacy of MYC/EZH2 dual targeting both in vitro and in vivo. Altogether, our results provide first pre-clinical evidence that simultaneous targeting of MYC and EZH2 is a safe and efficient approach that can be monitored by specific biomarkers, in aggressive lymphoid tumors of germinal center origin. |
| format | Article |
| id | doaj-art-09a75a3cd1a945aeb51e82b1c26b622d |
| institution | Kabale University |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-09a75a3cd1a945aeb51e82b1c26b622d2025-02-06T05:11:17ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-03-0161101131YPEL2 regulates the efficacy of BRD4-EZH2 dual targeting in EZH2Y641mut germinal center-derived lymphomaAránzazu Chamorro-Jorganes0Núria Profitós-Pelejà1Clara Recasens-Zorzo2Juan G Valero3Diana Reyes-Garau4Laura Magnano5Ray Butler6Antonio Postigo7Patricia Pérez-Galán8Marcelo Lima Ribeiro9Gaël Roué10Division of Hemato-oncology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainDivision of Hemato-oncology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Lymphoma Translational group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, SpainDivision of Hemato-oncology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainDivision of Hemato-oncology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red-Oncología (CIBERONC), Madrid, SpainLymphoma Translational group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, SpainDivision of Hemato-oncology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainButler Scientifics, Barcelona, SpainGroup of Gene Regulation of Stem Cells and Cell Plasticity, IDIBAPS, ICREA, Barcelona, SpainDivision of Hemato-oncology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red-Oncología (CIBERONC), Madrid, SpainLymphoma Translational group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain; Laboratory of Immunopharmacology and Molecular Biology, Sao Francisco University Medical School, Braganca Paulista, Sao Paulo, BrazilLymphoma Translational group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain; Corresponding author: Lymphoma Translational Group, Josep Carreras Leukaemia Research Institute, Badalona 08916, Spain.A significant proportion of diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) cases harbor a gain-of-function, heterozygous somatic mutation of the methyltransferase gene EZH2. While this factor is known to cooperate with the proto-oncogene MYC during malignant B cell development, the effect of interfering with both factors remains underexplored. Here we undertook the simultaneous evaluation of two epigenetic drugs targeting EZH2 methyltransferase activity and BRD4-mediated control of MYC transcription, CPI169 and CPI203, using preclinical models of DLBCL and FL with distinct EZH2 mutational status. We observed a specific and synergistic antiproliferative effect of these compounds in EZH2-mutated cells and mouse xenograft models, that was related to the abrogation of MYC transcriptional program and to tumor cell proliferation blockade at the G1 cell cycle phase. Gene expression profile, exploratory data analysis, and siRNA screening identified the PI3K/AKT-regulated gene and mitosis regulator, YPEL2, as a crucial factor involved in the efficacy of MYC/EZH2 dual targeting both in vitro and in vivo. Altogether, our results provide first pre-clinical evidence that simultaneous targeting of MYC and EZH2 is a safe and efficient approach that can be monitored by specific biomarkers, in aggressive lymphoid tumors of germinal center origin.http://www.sciencedirect.com/science/article/pii/S1476558625000107Non-Hodgkin lymphomaEpigeneticsTargeted therapiesBiomarkersMouse model |
| spellingShingle | Aránzazu Chamorro-Jorganes Núria Profitós-Pelejà Clara Recasens-Zorzo Juan G Valero Diana Reyes-Garau Laura Magnano Ray Butler Antonio Postigo Patricia Pérez-Galán Marcelo Lima Ribeiro Gaël Roué YPEL2 regulates the efficacy of BRD4-EZH2 dual targeting in EZH2Y641mut germinal center-derived lymphoma Neoplasia: An International Journal for Oncology Research Non-Hodgkin lymphoma Epigenetics Targeted therapies Biomarkers Mouse model |
| title | YPEL2 regulates the efficacy of BRD4-EZH2 dual targeting in EZH2Y641mut germinal center-derived lymphoma |
| title_full | YPEL2 regulates the efficacy of BRD4-EZH2 dual targeting in EZH2Y641mut germinal center-derived lymphoma |
| title_fullStr | YPEL2 regulates the efficacy of BRD4-EZH2 dual targeting in EZH2Y641mut germinal center-derived lymphoma |
| title_full_unstemmed | YPEL2 regulates the efficacy of BRD4-EZH2 dual targeting in EZH2Y641mut germinal center-derived lymphoma |
| title_short | YPEL2 regulates the efficacy of BRD4-EZH2 dual targeting in EZH2Y641mut germinal center-derived lymphoma |
| title_sort | ypel2 regulates the efficacy of brd4 ezh2 dual targeting in ezh2y641mut germinal center derived lymphoma |
| topic | Non-Hodgkin lymphoma Epigenetics Targeted therapies Biomarkers Mouse model |
| url | http://www.sciencedirect.com/science/article/pii/S1476558625000107 |
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