GSE109673 Dual inhibition of EZH1/2 depletes stem cells and over-activates WNT signaling in multiple myeloma [RNA-seq]

Contributors : Makoto Nakagawa ; Issay KitabayashiSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensMultiple myeloma (MM) is a hematological malignancy caused by accumulation of abnormal clonal plasma cells. Despite the recent development of novel therapies, relapse of MM eventually occurs due to a remaining population of drug-resistant myeloma stem cells. Side population (SP) cells exhibit cancer stem cell-like characteristics in MM; thus targeting these cells is a promising strategy to completely cure this malignancy. Here, we showed that SP cells expressed higher levels of enhancer of zeste (EZH) 1 and EZH2, which encode the catalytic subunits of Polycomb repressive complex 2 (PRC2), than non-SP cells, suggesting that EZH1/2 are both potential therapeutic targets to eradicate myeloma stem cells. A novel EZH1/2 dual inhibitor, OR-S1, effectively eradicated SP cells and had a greater antitumor effect than a selective EZH2 inhibitor in vitro and in vivo, including in a patient-derived xenograft model. Moreover, long-term continuous administration of OR-S1 completely cured mice bearing orthotopic xenografts. Additionally, PRC2 directly regulated WNT signaling, and over-activation of this signaling induced by dual inhibition of EZH1/2 eradicated myeloma stem cells. Our results demonstrate that dual inhibition of EZH1/2 is a promising therapeutic approach to eradicate myeloma stem cells, leading to significant advances in the treatment of M...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research