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

• Published in: Cancers Vol. 12; no. 9; p. 2541
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.09.2020; MDPI
• Subjects: Animal models; Apoptosis; B cells; B-cell lymphoma; Cell differentiation; Cell lineage; Cyclin-dependent kinases; Cytotoxicity; DLBCL; EZH2; Gene expression; Genome-wide association studies; Genomes; GSK126; Health aspects; Histone H3; Ikaros protein; IMiD; Kinases; Lymphocytes B; Lymphoma; Lymphomas; Lysine; Mutants; Mutation; Physiological aspects; Polycomb group proteins; pomalidomide; PRC2; Ribonucleic acid; RNA; Xenografts; Zinc finger proteins; South Korea
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers12092541

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.