title: The B-cell-activating factor signalling pathway is associated with Helicobacter pylori independence in gastric mucosa-associated lymphoid tissue lymphoma without t(11;18)(q21;q21).
abstract: We previously reported that activation of the B-cell-activating factor (BAFF) pathway upregulates nuclear factor-κB (NF-κB) and induces BCL3 and BCL10 nuclear translocation in Helicobacter pylori (HP)-independent gastric diffuse large B-cell lymphoma (DLBCL) tumours with evidence of mucosa-associated lymphoid tissue (MALT). However, the significance of BAFF expression in HP independence of gastric low-grade MALT lymphomas without t(11;18)(q21;q21) remains unexplored. Sixty-four patients who underwent successful HP eradication for localized HP-positive gastric MALT lymphomas without t(11;18)(q21;q21) were studied. BAFF expression was significantly higher in the HP-independent group than in the HP-dependent group [22/26 (84.6%) versus 8/38 (21.1%); p < 0.001]. Similarly, BAFF receptor (BAFF-R) expression (p = 0.004) and nuclear BCL3 (p = 0.004), BCL10 (p < 0.001), NF-κB (p65) (p = 0.001) and NF-κB (p52) (p = 0.005) expression were closely correlated with the HP independence of these tumours. Moreover, BAFF overexpression was significantly associated with BAFF-R expression and nuclear BCL3, BCL10, NF-κB (p65) and NF-κB (p52) expression. These findings were further validated in an independent cohort, including 40 HP-dependent cases and 18 HP-independent cases of gastric MALT lymphoma without t(11;18)(q21;q21). The biological significance of BAFF signalling in t(11;18)(q21;q21)-negative lymphoma cells was further studied in two types of lymphoma B cell: OCI-Ly3 [non-germinal centre B-cell origin DLBCL without t(11;18)(q21;q21) cell line] and MA-1 [t(14;18)(q32;q21)/IGH-MALT1-positive DLBCL cell line]. In both cell lines, we found that BAFF activated the canonical NF-κB and AKT pathways, and induced the formation of BCL10-BCL3 complexes, which translocated to the nucleus. BCL10 and BCL3 nuclear translocation and NF-κB (p65) transactivation were inhibited by either LY294002 or by silencing BCL3 or BCL10 with small interfering RNA. BAFF also activated non-canonical NF-κB pathways (p52) through tumour necrosis factor receptor-associated factor 3 degradation, NF-κB-inducing kinase accumulation, inhibitor of κB kinase (IKK) α/β phosphorylation and NF-κB p100 processing in both cell lines. Our data indicate that the autocrine BAFF signal transduction pathway contributes to HP independence in gastric MALT lymphomas without the t(11;18)(q21;q21) translocation. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei, Taiwan.|Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Sung-Hsin
authors.initials: SH
authors.lastname: Kuo
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.|Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Hui-Jen
authors.initials: HJ
authors.lastname: Tsai
authors.affiliation: Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chung-Wu
authors.initials: CW
authors.lastname: Lin
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.|National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei, Taiwan.|Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Kun-Huei
authors.initials: KH
authors.lastname: Yeh
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.|National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Hsiao-Wei
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.|Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Wei
authors.affiliation: Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chia-Tung
authors.initials: CT
authors.lastname: Shun
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ming-Shiang
authors.initials: MS
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ping-Ning
authors.initials: PN
authors.lastname: Hsu
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.|Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Internal Medicine, National Cheng-Kung University Hospital, Tainan, Taiwan.
authors.forename: Li-Tzong
authors.initials: LT
authors.lastname: Chen
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei, Taiwan.|Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.|National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000378:metabolism*; D005260:Female; D016480:Helicobacter pylori; D006801:Humans; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase
keywords: BAFF; BCL10; BCL3; Helicobacter pylori; NF-κB; mucosa-associated lymphoid tissue (MALT) lymphoma