Combination treatment with GSK126 and pomalidomide induces B-cell differentiation in EZH2 gain-of-function mutant diffuse large B-cell lymphoma

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Title
Combination treatment with GSK126 and pomalidomide induces B-cell differentiation in EZH2 gain-of-function mutant diffuse large B-cell lymphoma
Author(s)
Seongryul Park; Seung-Hyun Jo; Jong-Hwan Kim; Seon-Young Kim; J D Ha; J Y Hwang; Myeong Youl LeeJong Soon KangTae Su HanSung Goo Park; S Kim; Byoung Chul ParkJeong Hoon Kim
Bibliographic Citation
Cancers, vol. 12, no. 9, pp. 2541-2541
Publication Year
2020
Abstract
Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), the catalytic subunit of polycomb repressive complex 2 (PRC2), regulates genes involved in cell lineage and differentiation through methylating lysine 27 on histone H3 (H3K27me3). Recurrent gain-of-function mutations of EZH2 have been identified in various cancer types, in particular, diffuse large B-cell lymphoma (DLBCL), through large-scale genome-wide association studies and EZH2 depletion or pharmacological inhibition has been shown to exert an antiproliferative effect on cancer cells, both in vitro and in vivo. In the current study, a combination of pomalidomide and GSK126 synergistically inhibited the growth of EZH2 gain-of-function mutant Diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, this synergistic effect appeared to be dependent on cereblon (CRBN), a cellular receptor of pomalidomide, but not degradation of IKAROS family zinc finger 1 (IKZF1) or IKAROS family zinc finger 3 (IKZF3). RNA sequencing analyses revealed that co-treatment with GSK126 and pomalidomide induced specific gene sets involved in B-cell differentiation and apoptosis. Synergistic growth inhibition and B-cell differentiation were further validated in xenograft mouse models. Our collective results provide a molecular basis for the mechanisms underlying the combined therapeutic effects of PRC2 inhibitors and pomalidomide on EZH2-mutated DLBCL.
Keyword
PRC2EZH2GSK126pomalidomideIMiDDLBCLsynergistic effectcombination therapy
ISSN
2072-6694
Publisher
MDPI
DOI
http://dx.doi.org/10.3390/cancers12092541
Type
Article
Appears in Collections:
Korea Bioinformation Center > 1. Journal Articles
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
Division of Biomedical Research > Biotherapeutics Translational Research Center > 1. Journal Articles
Division of Biomedical Research > Disease Target Structure Research Center > 1. Journal Articles
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