[논문]Combination Treatment with GSK126 and Pomalidomide Induces B-Cell Differentiation in EZH2 Gain-of-Function Mutant Diffuse Large B-Cell Lymphoma

Park, Sungryul; Jo, Seung-Hyun; Kim, Jong-Hwan; Kim, Seon-Young; Ha, Jae Du; Hwang, Jong Yeon; Lee, Myeong Youl; Kang, Jong Soon; Han, Tae-Su; Park, Sung Goo; Kim, Sunhong; Park, Byoung Chul; Kim, Jeong-Hoon

doi:10.3390/cancers12092541

[해외논문] Combination Treatment with GSK126 and Pomalidomide Induces B-Cell Differentiation in EZH2 Gain-of-Function Mutant Diffuse Large B-Cell Lymphoma 원문보기

Cancers, v.12 no.9, 2020년, pp.2541 -

Park, Sungryul (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea) , Jo, Seung-Hyun (psrv92@kribb.re.kr (S.P.)) , Kim, Jong-Hwan (josh@kribb.re.kr (S.-H.J.)) , Kim, Seon-Young (sgpark@kribb.re.kr (S.G.P.)) , Ha, Jae Du (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea) , Hwang, Jong Yeon (psrv92@kribb.re.kr (S.P.)) , Lee, Myeong Youl (josh@kribb.re.kr (S.-H.J.)) , Kang, Jong Soon (sgpark@kribb.re.kr (S.G.P.)) , Han, Tae-Su (Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea) , Park, Sung Goo (kkjjhhk@kribb.re.kr) , Kim, Sunhong (KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Korea) , Park, Byoung Chul (kimsy@kribb.re.kr) , Kim, Jeong-Hoon (Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-606, Korea)

Abstract ▼ AI-Helper

Simple SummaryTo overcome the potential threat of drug resistance or limit of potency, the combination treatment of drugs is a promising strategy. Around 22% of patients with GCB-DLBCL carry EZH2 gain-of-function mutations and several PRC2 inhibitors are under clinical trials. Herein, we demonstrate that combination of GSK126 with pomalidomide synergistically inhibit tumor growth through inducing B-cell maturation and apoptosis in EZH2 gain-of-function mutant DLBCL. Our study provides the molecular basis of the combination strategy of PRC2 inhibitors and IMiDs in DLBCLs harboring EZH2 hyperactive mutation.AbstractEnhancer 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.

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