Expression of BAFF-R (BR3) in normal and neoplastic lymphoid tissues characterized with a newly developed monoclonal antibody

Nakamura, Naoya; Häse, H.; Sakurai, Daiju; Yoshida, Shigeaki; Abe, Masafumi; Tsukada, Nobuhiro; Takizawa, Jun; Aoki, Shin; Kojima, Masaru; Nakamura, Shigeo; Kobata, Tetsuji

doi:10.1007/s00428-005-1275-6

Cited by 32 publications

(33 citation statements)

References 39 publications

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“…34,36 Although the proteins that have a role in the pathogenesis of MALT lymphoma are still largely unknown (except for those involved in the NF-kB pathway), we compared the gastric MALT lymphoma expression patterns found in this study with the chromosomal locations of genes encoding proteins that are involved in the NF-kB pathway and/or proteins with previously reported altered expression in marginal zone lymphoma. [37][38][39][40][41][42][43][44][45][46] Of interest is that 18q21/MALT1 is overexpressed in all the three groups, consistent with reported MALT1 overexpression in MALT lymphomas regardless of the presence or absence of a t(11;18)(q21;q21). Overexpression of 11q21/ API2 did only occur in the two t(11;18)(q21;q21)-positive groups and not in the t(11;18)(q21;q21)-negative group and may be explained by API2-MALT-induced transcriptional activation of the API2 gene through NF-kB binding elements.…”

Section: Discussionsupporting

confidence: 75%

Comparative expressed sequence hybridization studies of t(11;18)(q21;q21)-positive and -negative gastric MALT lymphomas reveal both unique and overlapping gene programs

et al. 2010

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Among the genetic abnormalities reported to occur in MALT lymphomas, the translocation t(11;18)(q21;q21) is of particular interest because it is exclusively documented in MALT lymphomas, mainly with gastrointestinal location. It results in the creation of a fusion protein API2-MALT1 that activates the transcription factor NF-jB through enhanced IKKc polyubiquitination. Here, we apply the recently developed molecular technique termed comparative expressed sequence hybridization to identify differentially expressed chromosomal regions related to the pathogenesis of gastric MALT lymphomas. By comparing t(11;18)(q21;q21)-positive gastric MALT lymphomas to their t(11;18)(q21;q21)-negative counterparts, we found that the location of the MALT1 break point determines a difference in expression pattern within the t(11;18)(q21;q21)-positive group. Moreover, we could define a gastric MALT lymphoma signature, which most likely comprises the regions and genes with significance in the development of MALT lymphomas, by comparing both t(11;18)(q21;q21)-positive and -negative MALT lymphomas to normal lymphoid tissue. Finally, a significant imprint of the marginal zone signature, established by comparing microdissected, splenic B follicles with and without marginal zone, was evident in the expression profile of MALT lymphoma, further supporting a marginal zone origin for this type of B-cell non-Hodgkin's lymphoma.

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Section: Discussionsupporting

confidence: 75%

Comparative expressed sequence hybridization studies of t(11;18)(q21;q21)-positive and -negative gastric MALT lymphomas reveal both unique and overlapping gene programs

et al. 2010

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“…36 Lack of BAFF-R on HRS cells has been reported by others 73,74 and may result from the overall transcriptional down-regulation of B-cell-associated genes in HL tumors. [7][8][9][10] Of nonmalignant B cells, plasma cells expressed little or no BAFF-R, whereas GC B cells, the putative HRS precursor, expressed abundant BAFF-R.…”

Section: Discussionmentioning

confidence: 83%

Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF and APRIL

Chiu

et al. 2006

Blood

204

179

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IntroductionClassical Hodgkin lymphoma (HL) is a lymphoid neoplasm that stems from the clonal expansion of mononuclear Hodgkin cells and multinuclear Reed-Sternberg cells expressing the CD30 antigen. 1 Malignant Hodgkin and Reed-Sternberg (HRS) cells usually constitute less than 10% of the neoplastic mass. 2 The remaining tissue is composed of a reactive cellular infiltrate. Although rare cases with T-cell genotype have been described, 3,4 the vast majority of classical HL tumors is thought to originate from transformed germinal center (GC) B cells, because their HRS component harbors a monoclonal immunoglobulin (Ig) gene rearrangement and somatically mutated Ig V region genes. 1,[5][6][7] Despite their GC B-cell origin, HRS cells lack many molecules usually expressed by B cells and are incapable of producing functional Igs. [7][8][9][10][11][12] While nonmalignant B cells that have lost their capacity to express Igs rapidly undergo apoptosis, 13 malignant HRS cells survive. This abnormal survival is thought to be due to dysregulated activation of nuclear factor B (NF-B), 14-18 a transcription factor essential for the development of both normal and neoplastic B cells. 19,20 In classical HL, the reactive infiltrate is composed of nonmalignant T cells, B cells, plasma cells, and myeloid cells, including macrophages and granulocytes. 2,21 These cells are thought to enhance HRS cell growth through cytokines and tumor necrosis factor (TNF) family members, such as CD30 ligand (CD30L), receptor activator of NF-B ligand (RANKL), and CD40 ligand (CD40L). 15,[22][23][24][25][26][27][28][29] Recent studies show that myeloid cells express B-cell-activating factor of the TNF family (BAFF, also known as BLyS) and its homolog APRIL, a proliferation-inducing ligand, [30][31][32][33] 2 molecules essential for the survival, proliferation, and differentiation of B cells and plasma cells. 34,35 BAFF activates B cells and plasma cells by binding to transmembrane activator and calcium modulator and cyclophylin ligand interactor (TACI), B-cell maturation antigen (BCMA), and BAFF receptor (BAFF-R) receptors. APRIL activates B cells and plasma cells by binding to TACI and BCMA, but not BAFF-R. 36 By recruiting TNF receptor-associated factor (TRAF) adaptor molecules, TACI, BCMA, and BAFF-R activate an IB kinase (IKK) complex that in turn elicits phosphorylation-dependent degradation of inhibitor of NF-B (IB), which retains p50, c-Rel, and p65 NF-B proteins in a cytoplasmic inactive form. [37][38][39] IB degradation causes NF-B nuclear translocation and transcriptional activation of NF-B-responsive genes involved in B-cell survival, proliferation, and maturation. 31,[39][40][41] Of note, recent studies show that APRIL signaling via TACI and BCMA receptors is reinforced by heparan sulfate proteoglycans (HSPGs) anchored on the cell membrane or associated with the extracellular matrix. 35,42,43 The role of TACI, BCMA, BAFF-R, and HSPGs in HL remains unknown.BAFF and APRIL are implicated in B-cell neoplasias, 44-52 including non-Hodgkin lymph...

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“…BLyS is crucial for B-cell survival, and the biological effects of BLyS are mediated by three cell surface receptors designated BAFF-R, TACI, and BCMA (11 -13). BAFF-R is expressed in about 80% of MCL and in about 44% of DLBCL (15). It therefore seems that targeting BLyS and its receptors may disrupt this important autocrine growth loop in B-cell malignancies.…”

Section: Discussionmentioning

confidence: 99%

“…BAFF-R is expressed in about 80% of mantle cell lymphoma (MCL; ref. 15), a B-cell malignancy capable of developing rapid resistance to conventional chemotherapeutic regimens.…”

Section: Introductionmentioning

confidence: 99%

The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA

Lyu

Cheung

Hittelman

et al. 2007

Molecular Cancer Therapeutics

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B lymphocyte stimulator (BLyS) is crucial for B-cell survival, and the biological effects of BLyS are mediated by three cell surface receptors designated B cellactivating factor receptor (BAFF-R), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and B-cell maturation antibody (BCMA). Increased expression of BLyS and its receptors has been identified in numerous B-cell malignancies. We generated a fusion toxin designated rGel/BLyS for receptor-mediated delivery of the recombinant gelonin (rGel) toxin to neoplastic B cells, and we characterized its activity against various B-cell tumor lines. Three mantle cell lymphoma (MCL) cell lines (JeKo-1, Mino, and SP53) and two diffuse large B-cell lymphoma (DLBCL) cell lines (SUDHL-6 and OCI-Ly3) expressing all three distinct BLyS receptors were found to be the most sensitive to the fusion toxin (IC 50 = 2 -5 pmol/L and 0.001 -5 nmol/L for MCL and DLBCL, respectively). The rGel/BLyS fusion toxin showed specific binding to cells expressing BLyS receptors and rapid internalization of the rGel component into target cells. The cytotoxic effects of rGel/BLyS were inhibited by pretreatment with free BLyS or with soluble BAFF-R, TACI, and BCMA decoy receptors. This suggests that the cytotoxic effects of the fusion toxin are mediated through BLyS receptors. The rGel/BLyS fusion toxin inhibited MCL cell growth through induction of apoptosis associated with caspase-3 activation and poly (ADP-ribose) polymerase cleavage. Our results suggest that BLyS has the potential to serve as an excellent targeting ligand for the specific delivery of cytotoxic molecules to neoplastic B cells expressing the BLyS receptors, and that the rGel/ BLyS fusion toxin may be an excellent candidate for the treatment of B-cell malignancies especially MCL and DLBCL. [Mol Cancer Ther 2007;6(2):460 -70]

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Expression of BAFF-R (BR3) in normal and neoplastic lymphoid tissues characterized with a newly developed monoclonal antibody

Cited by 32 publications

References 39 publications

Comparative expressed sequence hybridization studies of t(11;18)(q21;q21)-positive and -negative gastric MALT lymphomas reveal both unique and overlapping gene programs

Comparative expressed sequence hybridization studies of t(11;18)(q21;q21)-positive and -negative gastric MALT lymphomas reveal both unique and overlapping gene programs

Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF and APRIL

The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA

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