| Literature DB >> 29045832 |
Teresa Ezponda1, Daphné Dupéré-Richer2, Christine M Will1, Eliza C Small1, Nobish Varghese1, Tej Patel1, Behnam Nabet1, Relja Popovic1, Jon Oyer1, Marinka Bulic1, Yupeng Zheng3, Xiaoxiao Huang4, Mrinal Y Shah1, Sayantan Maji2, Alberto Riva5, Manuela Occhionorelli6, Giovanni Tonon6, Neil Kelleher4, Jonathan Keats7, Jonathan D Licht8.
Abstract
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.Entities:
Keywords: BCL6; EZH2 inhibitors; H3K27me3; IRF4; KDM6A; PRC2; UTX; epigenetic regulator; multiple myeloma
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Year: 2017 PMID： 29045832 PMCID： PMC5706555 DOI： 10.1016/j.celrep.2017.09.078
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423