UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibition
Loss or inactivation of the histone H3K27 demethylase UTX occurs in several malignancies, including multiple myeloma (MM). Using an isogenic cell system, we found that loss of UTX leads to deactivation of gene expression ultimately promoting the proliferation, clonogenicity, adhesion, and tumorigeni...
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Elsevier
2017-10-01
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Series: | Cell Reports |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717313839 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Teresa Ezponda Daphné Dupéré-Richer Christine M. Will Eliza C. Small Nobish Varghese Tej Patel Behnam Nabet Relja Popovic Jon Oyer Marinka Bulic Yupeng Zheng Xiaoxiao Huang Mrinal Y. Shah Sayantan Maji Alberto Riva Manuela Occhionorelli Giovanni Tonon Neil Kelleher Jonathan Keats Jonathan D. Licht |
spellingShingle |
Teresa Ezponda Daphné Dupéré-Richer Christine M. Will Eliza C. Small Nobish Varghese Tej Patel Behnam Nabet Relja Popovic Jon Oyer Marinka Bulic Yupeng Zheng Xiaoxiao Huang Mrinal Y. Shah Sayantan Maji Alberto Riva Manuela Occhionorelli Giovanni Tonon Neil Kelleher Jonathan Keats Jonathan D. Licht UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibition Cell Reports multiple myeloma UTX KDM6A EZH2 inhibitors IRF4 BCL6 PRC2 H3K27me3 epigenetic regulator |
author_facet |
Teresa Ezponda Daphné Dupéré-Richer Christine M. Will Eliza C. Small Nobish Varghese Tej Patel Behnam Nabet Relja Popovic Jon Oyer Marinka Bulic Yupeng Zheng Xiaoxiao Huang Mrinal Y. Shah Sayantan Maji Alberto Riva Manuela Occhionorelli Giovanni Tonon Neil Kelleher Jonathan Keats Jonathan D. Licht |
author_sort |
Teresa Ezponda |
title |
UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibition |
title_short |
UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibition |
title_full |
UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibition |
title_fullStr |
UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibition |
title_full_unstemmed |
UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibition |
title_sort |
utx/kdm6a loss enhances the malignant phenotype of multiple myeloma and sensitizes cells to ezh2 inhibition |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2017-10-01 |
description |
Loss or inactivation of the histone H3K27 demethylase UTX occurs in several malignancies, including multiple myeloma (MM). Using an isogenic cell system, we found that loss of UTX leads to deactivation of gene expression ultimately promoting the proliferation, clonogenicity, adhesion, and tumorigenicity of MM cells. Moreover, UTX mutant cells showed increased in vitro and in vivo sensitivity to inhibition of EZH2, a histone methyltransferase that generates H3K27me3. Such sensitivity was related to a decrease in the levels of IRF4 and c-MYC and an activation of repressors of IRF4 characteristic of germinal center B cells such as BCL6 and IRF1. Rebalance of H3K27me3 levels at specific genes through EZH2 inhibitors may be a therapeutic strategy in MM cases harboring UTX mutations. |
topic |
multiple myeloma UTX KDM6A EZH2 inhibitors IRF4 BCL6 PRC2 H3K27me3 epigenetic regulator |
url |
http://www.sciencedirect.com/science/article/pii/S2211124717313839 |
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doaj-c8e4f4dce46b4e28975494365da80fbf2020-11-25T01:17:03ZengElsevierCell Reports2211-12472017-10-0121362864010.1016/j.celrep.2017.09.078UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibitionTeresa Ezponda0Daphné Dupéré-Richer1Christine M. Will2Eliza C. Small3Nobish Varghese4Tej Patel5Behnam Nabet6Relja Popovic7Jon Oyer8Marinka Bulic9Yupeng Zheng10Xiaoxiao Huang11Mrinal Y. Shah12Sayantan Maji13Alberto Riva14Manuela Occhionorelli15Giovanni Tonon16Neil Kelleher17Jonathan Keats18Jonathan D. Licht19Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADivision of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, FL 2033, USADivision of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADivision of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADivision of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADivision of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADivision of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADivision of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADivision of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADivision of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADepartment of Chemistry, Department of Molecular Biosciences, and the Proteomics Center of Excellence, Northwestern University, Evanston, IL 60208, USADivision of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADivision of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USADivision of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, FL 2033, USABioinformatics Core, Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, FL 2033, USAFunctional Genomics of Cancer Unit, Division of Molecular Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan 70126, ItalyFunctional Genomics of Cancer Unit, Division of Molecular Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan 70126, ItalyDivision of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USATranslational Genomics Research Institute (TGen), Phoenix, AZ 85004, USADivision of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USALoss or inactivation of the histone H3K27 demethylase UTX occurs in several malignancies, including multiple myeloma (MM). Using an isogenic cell system, we found that loss of UTX leads to deactivation of gene expression ultimately promoting the proliferation, clonogenicity, adhesion, and tumorigenicity of MM cells. Moreover, UTX mutant cells showed increased in vitro and in vivo sensitivity to inhibition of EZH2, a histone methyltransferase that generates H3K27me3. Such sensitivity was related to a decrease in the levels of IRF4 and c-MYC and an activation of repressors of IRF4 characteristic of germinal center B cells such as BCL6 and IRF1. Rebalance of H3K27me3 levels at specific genes through EZH2 inhibitors may be a therapeutic strategy in MM cases harboring UTX mutations.http://www.sciencedirect.com/science/article/pii/S2211124717313839multiple myelomaUTXKDM6AEZH2 inhibitorsIRF4BCL6PRC2H3K27me3epigenetic regulator |