GSE123518 A novel target of EZH1/2 for treatment of mantle cell lymphoma

Contributors : Yuki Kagiyama ; Issay KitabayashiSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensMantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin ’s lymphoma, which is characterized by the translocation of t(11:14)(q13;q32) resulting in overexpression of cyclin D1. Patients with MCL often acquire resistance to conventional chemotherapy such as R-CHOP, BR, and ibrutinib. Therefore, novel therapeutic targets for relapsed MCL are needed. EZH1/ 2 are catalytic components of PRC2, which trimethylates H3K27 to repress transcription of target genes and play critical roles in B-cell development. Mutation and overexpression of EZH1/2 are associated with hematopoietic malignancies. Here, we examined whether inhibition of EZH1/2 had an antitumor effect on aggressive MCL cells. In a patient-derived xenograft model of MCL, EZH1/2 dual inhibitor OR-S1 treatment by oral administration significantly inhibited MCL tumor growth. Comprehensive gene expression analysis also indicated that the expression of genes related to cell cycle and cell differ entiation was changed in OR-S1-sensitive cell lines. Interestingly, CDKN1C, which contributes to cell cycle arrest, was up-regulated with decreased H3K27 trimethylation by OR-S1 treatment. Furthermore, knockout of CDKN1C by CRISPR-Cas9 decreased the sensitivity to OR-S1. These results suggest that E ZH1/2 may control MCL tumor growth and be a potential target for the treatment of aggressive MCL.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research