title: Diffuse large B-cell lymphoma with histone H3 trimethylation at lysine 27: another poor prognostic phenotype independent of c-Myc/Bcl2 coexpression.
abstract: Deregulation of histone H3 trimethylation at lysine 27 (H3K27me3) via aberration of the histone methyltransferase, enhancer of zeste homologue 2 (EZH2), is suggested to play a critical role in cancers including hematologic malignancies. In the present study, implications of H3K27me3 were investigated in diffuse large B-cell lymphoma (DLBCL) with respect to clinicopathological factors, especially in association with c-Myc/Bcl2 coexpression and germinal center B-like (GCB) or non-GCB subtype. By immunohistochemistry, a high level of H3K27me3 was observed in approximately one-third (35.3%, 79/224) of DLBCL cases, and this subset of cases was related to poor performance status (Eastern Cooperative Oncology Group scores ≥ 2) (P = .013), elevated lactate dehydrogenase level (P = .001), and a higher international prognostic index risk group (scores ≥3) (P = .005). H3K27me3 level was significantly correlated with EZH2 expression (P = .004) and c-Myc protein expression (P = .003) but not correlated with c-Myc/Bcl2 coexpression or with GCB or non-GCB subtype. A high level of H3K27me3 was related to an inferior overall survival (P = .006) and was shown to be an independent prognostic factor for overall survival along with the higher international prognostic index risk group and c-Myc/Bcl2 coexpression. In conclusion, H3K27me3 was related to EZH2 and c-Myc expression, suggesting formation of a MYC-EZH2-H3K27me3 loop in a subgroup of DLBCL cases. H3K27me3 was associated with poor patient outcome and revealed as an independent predictor for overall survival of DLBCL patients. H3K27me3 in DLBCL may be another high-risk phenotype independent of the phenotype of c-Myc/Bcl2 coexpression or other known poor prognostic subgroups.
authors.affiliation: Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Oh
authors.affiliation: Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Woo Ick
authors.initials: WI
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: June-Won
authors.initials: JW
authors.lastname: Cheong
authors.affiliation: Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Choi
authors.affiliation: Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: revita@naver.com.
authors.forename: Sun Och
authors.initials: SO
authors.lastname: Yoon
mesh_terms: D000368:Aged; D019175:DNA Methylation / Q000502:physiology*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008239:Lysine / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D063151:Polycomb Repressive Complex 2 / Q000096:biosynthesis; D011379:Prognosis; D016016:Proportional Hazards Models; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D046888:Tissue Array Analysis
chemical_list: D006657:Histones; C489427:MYC protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D008239:Lysine
keywords: Bcl2; Histone H3 trimethylation at lysine 27; Lymphoma, large B-cell, diffuse; Prognosis; c-Myc