Expression and DNA methylation profiles of EZH2-target genes in plasma exosomes and matched primary tumor tissues of the
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RESEARCH ARTICLE
Expression and DNA methylation profiles of EZH2‑target genes in plasma exosomes and matched primary tumor tissues of the patients with diffuse large B‑cell lymphoma I. C. Barıs1 · S. Hacıoglu2 · N. S. Turk3 · G. O. Cetın4 · S. Zencır1,5 · G. Bagcı4 · V. Caner4 Received: 18 July 2020 / Accepted: 19 September 2020 © Federación de Sociedades Españolas de Oncología (FESEO) 2020
Abstract Aims Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoma. This study was designed to compare epigenetic alterations observed in Enhancer of Zeste Homolog 2 (EZH2)-target genes between plasma-derived exosomes and primary tumors in DLBCL patients. Main methods Exosomes were isolated from plasma of 21 DLBCL patients and 21 controls. We analyzed the methylation status of the target genes using methylation-specific PCR. We also examined whether the exosomes and the tumor samples contained transcripts of the target genes. Key findings We found that CDKN2A and CDKN2B were methylated in both plasma exosomes and primary tumor tissue samples. None of the transcripts were found in the exosomes except CDKN1B which was expressed in 8 (38%) of the exosome samples. Significance This study showed that plasma exosomes might preferably package certain target molecules from primary tumors and the exosomes containing dual methylated DNAs of CDKN2A and CDKN2B, or CDKN1B transcript may contribute to DLBCL pathogenesis. Keywords Diffuse large B-cell lymphoma · Epigenetics · EZH2-target genes · Exosome
Introduction Diffuse large B-cell lymphoma (DLBCL) is the most commonly observed type of non-Hodgkin’s lymphoma (NHL), which accounts for approximately 30–40% of lymphomas. In Turkey, NHL is the eighth most common cancer in women and the seventh most common cancer in men although there * V. Caner [email protected] 1
Department of Medical Biology, School of Medicine, Pamukkale University, Denizli, Turkey
2
Department of Hematology, School of Medicine, Pamukkale University, Denizli, Turkey
3
Department of Medical Pathology, School of Medicine, Pamukkale University, Denizli, Turkey
4
Department of Medical Genetics, School of Medicine, Pamukkale University, Denizli, Turkey
5
Present Address: Department of Molecular Biology, University of Geneva, 1211 Geneva 4, Switzerland
is no specific statistical data for DLBCL [1]. Several signaling pathways have been found to contribute to DLBCL development [2–4], but the exact pathogenesis of the lymphoma still remains unclear. EZH2 catalyzes the trimethylation of the 27th lysine residue of the histone protein 3 (H3) (H3K27me3). EZH2-mediated H3K27me3 activity is responsible for the maintenance of bivalent chromatin domains which is characterized by the combination of suppressive marker H3K27me3 and the activating marker H3K4me3 in gene promoters. There are at least 2 different pathways involved in EZH2-mediated lymphomagenesis. Oncogenic gain-of-function EZH2 mutations are responsible for the methylation-independent pathway and the tyrosine 641 (Y641
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