gsk343 and Multiple-Myeloma

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.

Topics: Animals; Carcinogenesis; Cell Adhesion; Cell Dedifferentiation; Cell Line, Tumor; Cell Proliferation; Cell Survival; Clone Cells; Enhancer of Zeste Homolog 2 Protein; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Histone Demethylases; Histones; Indazoles; Interferon Regulatory Factors; Lysine; Methylation; Mice; Mice, Inbred NOD; Mice, SCID; Multiple Myeloma; Mutation; Nuclear Proteins; Phenotype; Pyridones; Transcription, Genetic