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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

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. Ezponda et al. now demonstrate how the loss of UTX/KDM6A, a factor that regulates chromatin, contributes to multiple myeloma, conferring malignant properties to these cells. Moreover, they show how the use of EZH2 inhibitors, currently in clinical trials, specifically affect MM cells harboring UTX loss.

Original languageEnglish (US)
Pages (from-to)628-640
Number of pages13
JournalCell reports
Volume21
Issue number3
DOIs
StatePublished - Oct 17 2017

Keywords

  • BCL6
  • EZH2 inhibitors
  • H3K27me3
  • IRF4
  • KDM6A
  • PRC2
  • UTX
  • epigenetic regulator
  • multiple myeloma

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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