Open AccessFrequent downregulation of BTB and CNC homology 2 expression in Epstein–Barr virus‐positive diffuse large B‐cell lymphoma
Author(s) -
NoujimaHarada Mai,
Takata Katsuyoshi,
MiyataTakata Tomoko,
Sakurai Hiroaki,
Igarashi Kazuhiko,
Ito Etsuro,
Nagakita Keina,
Taniguchi Kohei,
Ohnishi Nobuhiko,
Omote Shizuma,
Tabata Tetsuya,
Sato Yasuharu,
Yoshino Tadashi
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13213
Subject(s) - downregulation and upregulation , lymphoma , epstein–barr virus , diffuse large b cell lymphoma , immunohistochemistry , cancer research , biology , western blot , microbiology and biotechnology , virus , pathology , medicine , virology , immunology , gene , biochemistry
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 ( BACH 2) has been highlighted as a tumor suppressor in hematopoietic malignancies; however, the role of BACH 2 in EBV ‐positive DLBCL is unclear. In the present study, BACH 2 expression and its significance were studied in 23 EBV ‐positive and 43 EBV ‐negative patient samples. Immunohistochemistry revealed BACH 2 downregulation in EBV ‐positive cases ( P < 0.0001), although biallelic deletion of BACH 2 was not detected by FISH . Next, we analyzed the contribution of BACH 2 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 BACH 2 ‐transfected FL ‐18‐ EB cells, downregulation of phosphorylated transforming growth factor‐β‐activated kinase 1 ( pTAK 1) and suppression in p65 nuclear fractions were observed by Western blot analysis contrary to non‐transfected FL ‐18‐ EB cells. In patient samples, pTAK 1 expression and significant nuclear p65, p50, and p52 localization were detected immunohistochemically in BACH 2‐negative DLBCL ( P < 0.0001, P = 0.006, and P = 0.001, respectively), suggesting that BACH 2 downregulation contributes to constitutive activation of the nuclear factor‐κB pathway through TAK 1 phosphorylation in BACH 2‐negative DLBCL (most EBV ‐positive cases). Although further molecular and pathological studies are warranted to clarify the detailed mechanisms, downregulation of BACH 2 may contribute to constitutive activation of the nuclear factor‐κB pathway through TAK 1 activation.