title: Frequent downregulation of BTB and CNC homology 2 expression in Epstein-Barr virus-positive diffuse large B-cell lymphoma.
abstract: Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell lymphoma subtype, and the Epstein-Barr virus (EBV)-positive subtype of DLBCL is known to show a more aggressive clinical behavior than the EBV-negative one. BTB and CNC homology 2 (BACH2) has been highlighted as a tumor suppressor in hematopoietic malignancies; however, the role of BACH2 in EBV-positive DLBCL is unclear. In the present study, BACH2 expression and its significance were studied in 23 EBV-positive and 43 EBV-negative patient samples. Immunohistochemistry revealed BACH2 downregulation in EBV-positive cases (P < 0.0001), although biallelic deletion of BACH2 was not detected by FISH. Next, we analyzed the contribution of BACH2 negativity to aggressiveness in EBV-positive B-cell lymphomas using FL-18 (EBV-negative) and FL-18-EB cells (FL-18 sister cell line, EBV-positive). In BACH2-transfected FL-18-EB cells, downregulation of phosphorylated transforming growth factor-β-activated kinase 1 (pTAK1) and suppression in p65 nuclear fractions were observed by Western blot analysis contrary to non-transfected FL-18-EB cells. In patient samples, pTAK1 expression and significant nuclear p65, p50, and p52 localization were detected immunohistochemically in BACH2-negative DLBCL (P < 0.0001, P = 0.006, and P = 0.001, respectively), suggesting that BACH2 downregulation contributes to constitutive activation of the nuclear factor-κB pathway through TAK1 phosphorylation in BACH2-negative DLBCL (most EBV-positive cases). Although further molecular and pathological studies are warranted to clarify the detailed mechanisms, downregulation of BACH2 may contribute to constitutive activation of the nuclear factor-κB pathway through TAK1 activation.
authors.affiliation: Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Noujima-Harada
authors.affiliation: Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Katsuyoshi
authors.identifier: http://orcid.org/0000-0001-6890-1276
authors.initials: K
authors.lastname: Takata
authors.affiliation: Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Miyata-Takata
authors.affiliation: Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, Toyama University, Toyama, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sakurai
authors.affiliation: Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Igarashi
authors.affiliation: Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Etsuro
authors.initials: E
authors.lastname: Ito
authors.affiliation: Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Keina
authors.initials: K
authors.lastname: Nagakita
authors.affiliation: Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Taniguchi
authors.affiliation: Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Ohnishi
authors.affiliation: Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Shizuma
authors.initials: S
authors.lastname: Omote
authors.affiliation: Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tabata
authors.affiliation: Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshino
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D015536:Down-Regulation / Q000502:physiology*; D020031:Epstein-Barr Virus Infections / Q000378:metabolism / Q000821:virology; D005260:Female; D004854:Herpesvirus 4, Human / Q000472:pathogenicity; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism* / Q000821:virology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D055815:Young Adult
chemical_list: C491123:BACH2 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D016328:NF-kappa B; D051996:Transcription Factor RelA; D020930:MAP Kinase Kinase Kinases
keywords: BACH2; Epstein-Barr virus; NFκB; TAK1; diffuse large B-cell lymphoma