UTX/KDM6A Loss Enhances the Malignant Phenotype of Multiple Myeloma and Sensitizes Cells to EZH2 inhibition

Cell Reports

Alberto Riva¹  Yupeng Zheng²  Relja Popovic³  Jonathan D. Licht³  Nobish Varghese³  Behnam Nabet³  Jon Oyer³  Mrinal Y. Shah³  Xiaoxiao Huang³  Tej Patel³  Marinka Bulic³  Teresa Ezponda³  Christine M. Will³  Neil Kelleher³  Eliza C. Small³  Daphné Dupéré-Richer⁴  Sayantan Maji⁴  Giovanni Tonon⁵  Manuela Occhionorelli⁵  Jonathan Keats⁶ 

[1] Bioinformatics Core, Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, FL 2033, USA;Department of Chemistry, Department of Molecular Biosciences, and the Proteomics Center of Excellence, Northwestern University, Evanston, IL 60208, USA;Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA;Division of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, FL 2033, USA;Functional Genomics of Cancer Unit, Division of Molecular Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan 70126, Italy;Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA;

关键词: multiple myeloma;    UTX;    KDM6A;    EZH2 inhibitors;    IRF4;    BCL6;    PRC2;    H3K27me3;    epigenetic regulator;   

DOI  :  10.1016/j.celrep.2017.09.078

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown