Skip to main content
Erschienen in: Journal of Neuro-Oncology 2/2015

01.01.2015 | Laboratory Investigation

Differential expression of Toll-like receptor (TLR) and B cell receptor (BCR) signaling molecules in primary diffuse large B-cell lymphoma of the central nervous system

verfasst von: Ariz Akhter, Noraidah Masir, Ghaleb Elyamany, Kean-Chang Phang, Etienne Mahe, Ali Matar Al-Zahrani, Meer-Taher Shabani-Rad, Douglas Allan Stewart, Adnan Mansoor

Erschienen in: Journal of Neuro-Oncology | Ausgabe 2/2015

Einloggen, um Zugang zu erhalten

Abstract

Primary diffuse large B-cell lymphoma of the central nervous system (CNS DLBCL) is a distinct and aggressive lymphoma that is confined to CNS. Since, central nervous system is barrier-protected and immunologically silent; role of TLR/BCR signaling in pathogenesis and biology of CNS DLBCL is intriguing. Genomic mutations in key regulators of TLR/BCR signaling pathway (MYD88/CD79B/CARD11) have recently been reported in this disease. These observations raised possible implications in novel targeted therapies; however, expression pattern of molecules related to TLR/BCR pathways in this lymphoma remains unknown. We have analyzed the expression of 19 genes encoding TLR/BCR pathways and targets in CNS DLBCLs (n = 20) by Nanostring nCounter™ analysis and compared it with expression patterns in purified reactive B-lymphocytes and systemic diffuse large B cell lymphoma (DLBCL) (n = 20). Relative expression of TLR4, TLR5, TLR9, CD79B and BLNK was higher in CNS DLBCLs than in control B-lymphocytes; where as TLR7, MALT1, BCL10, CD79A and LYN was lower in CNS DLBCLs (P < 0.0001). When compared with systemic DLBCL samples, higher expression of TLR9, CD79B, CARD11, LYN and BLNK was noted in CNS DLBCL (>1.5 fold change; P < 0.01). The B cell receptor molecules like BLNK and CD79B were also associated with higher expression of MYD88 dependent TLRs (TLR4/5/9). In conclusion, we have shown over expression of TLR/BCR related genes or their targets, where genomic mutations have commonly been identified in CNS DLBCL. We have also demonstrated that TLR over expression closely relate with up regulation of genes associated with BCR pathway like CD79B/BLNK and CARD11, which play an important role in NF-kB pathway activation. Our results provide an important insight into the possibility of TLR and/or B-cell receptor signaling molecules as possible therapeutic targets in CNS DLBCL.
Literatur
1.
Zurück zum Zitat Kluin PDM, Ferry JA (2008) Primary diffuse large B-cell lymphoma of the CNS. In: Swerdlow SH, Campo E, Harris NL et al (eds) WHO classification of tumours of haematopoietic and lymphoid tissues. IARC, Lyon, pp 240–241 Kluin PDM, Ferry JA (2008) Primary diffuse large B-cell lymphoma of the CNS. In: Swerdlow SH, Campo E, Harris NL et al (eds) WHO classification of tumours of haematopoietic and lymphoid tissues. IARC, Lyon, pp 240–241
3.
Zurück zum Zitat Thiel E, Korfel A, Martus P, Kanz L, Griesinger F, Rauch M, Röth A, Hertenstein B, von Toll T, Hundsberger T, Mergenthaler HG, Leithäuser M, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Plasswilm L, Nägele T, Pietsch T, Bamberg M, Weller M (2010) High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. Lancet Oncol 11(11):1036–1047PubMedCrossRef Thiel E, Korfel A, Martus P, Kanz L, Griesinger F, Rauch M, Röth A, Hertenstein B, von Toll T, Hundsberger T, Mergenthaler HG, Leithäuser M, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Plasswilm L, Nägele T, Pietsch T, Bamberg M, Weller M (2010) High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. Lancet Oncol 11(11):1036–1047PubMedCrossRef
5.
Zurück zum Zitat Jordanova ES, Riemersma SA, Philippo K, Giphart-Gassler M, Schuuring E, Kluin PM (2002) Hemizygous deletions in the HLA region account for loss of heterozygosity in the majority of diffuse large B-cell lymphomas of the testis and the central nervous system. Genes Chromosom Cancer 35:38–48. doi:10.1002/gcc.10093 PubMedCrossRef Jordanova ES, Riemersma SA, Philippo K, Giphart-Gassler M, Schuuring E, Kluin PM (2002) Hemizygous deletions in the HLA region account for loss of heterozygosity in the majority of diffuse large B-cell lymphomas of the testis and the central nervous system. Genes Chromosom Cancer 35:38–48. doi:10.​1002/​gcc.​10093 PubMedCrossRef
6.
Zurück zum Zitat Rubenstein JL, Fridlyand J, Shen A, Aldape K, Ginzinger D, Batchelor T, Treseler P, Berger M, McDermott M, Prados M, Karch J, Okada C, Hyun W, Parikh S, Haqq C, Shuman M (2006) Gene expression and angiotropism in primary CNS lymphoma. Blood 107:3716–3723. doi:10.1182/blood-2005-03-0897 PubMedCentralPubMedCrossRef Rubenstein JL, Fridlyand J, Shen A, Aldape K, Ginzinger D, Batchelor T, Treseler P, Berger M, McDermott M, Prados M, Karch J, Okada C, Hyun W, Parikh S, Haqq C, Shuman M (2006) Gene expression and angiotropism in primary CNS lymphoma. Blood 107:3716–3723. doi:10.​1182/​blood-2005-03-0897 PubMedCentralPubMedCrossRef
8.
Zurück zum Zitat Booman M, Szuhai K, Rosenwald A, Hartmann E, Kluin-Nelemans H, de Jong D, Schuuring E, Kluin P (2008) Genomic alterations and gene expression in primary diffuse large B-cell lymphomas of immune-privileged sites: the importance of apoptosis and immunomodulatory pathways. J Pathol 216:209–217. doi:10.1002/path.2399 PubMedCrossRef Booman M, Szuhai K, Rosenwald A, Hartmann E, Kluin-Nelemans H, de Jong D, Schuuring E, Kluin P (2008) Genomic alterations and gene expression in primary diffuse large B-cell lymphomas of immune-privileged sites: the importance of apoptosis and immunomodulatory pathways. J Pathol 216:209–217. doi:10.​1002/​path.​2399 PubMedCrossRef
10.
Zurück zum Zitat Deckert M, Engert A, Bruck W, Ferreri AJ, Finke J, Illerhaus G, Klapper W, Korfel A, Kuppers R, Maarouf M, Montesinos-Rongen M, Paulus W, Schlegel U, Lassmann H, Wiestler OD, Siebert R, DeAngelis LM (2011) Modern concepts in the biology, diagnosis, differential diagnosis and treatment of primary central nervous system lymphoma. Leukemia 25:1797–1807. doi:10.1038/leu.2011.169 PubMedCrossRef Deckert M, Engert A, Bruck W, Ferreri AJ, Finke J, Illerhaus G, Klapper W, Korfel A, Kuppers R, Maarouf M, Montesinos-Rongen M, Paulus W, Schlegel U, Lassmann H, Wiestler OD, Siebert R, DeAngelis LM (2011) Modern concepts in the biology, diagnosis, differential diagnosis and treatment of primary central nervous system lymphoma. Leukemia 25:1797–1807. doi:10.​1038/​leu.​2011.​169 PubMedCrossRef
11.
Zurück zum Zitat Montesinos-Rongen M, Schafer E, Siebert R, Deckert M (2012) Genes regulating the B cell receptor pathway are recurrently mutated in primary central nervous system lymphoma. Acta Neuropathol 124:905–906. doi:10.1007/s00401-012-1064-7 PubMedCrossRef Montesinos-Rongen M, Schafer E, Siebert R, Deckert M (2012) Genes regulating the B cell receptor pathway are recurrently mutated in primary central nervous system lymphoma. Acta Neuropathol 124:905–906. doi:10.​1007/​s00401-012-1064-7 PubMedCrossRef
12.
Zurück zum Zitat Montesinos-Rongen M, Godlewska E, Brunn A, Wiestler OD, Siebert R, Deckert M (2011) Activating L265P mutations of the MYD88 gene are common in primary central nervous system lymphoma. Acta Neuropathol 122:791–792PubMedCrossRef Montesinos-Rongen M, Godlewska E, Brunn A, Wiestler OD, Siebert R, Deckert M (2011) Activating L265P mutations of the MYD88 gene are common in primary central nervous system lymphoma. Acta Neuropathol 122:791–792PubMedCrossRef
13.
Zurück zum Zitat O’Neill LA (2002) Signal transduction pathways activated by the IL-1 receptor/Toll-like receptor superfamily. Curr Top Microbiol Immunol 270:47–61PubMed O’Neill LA (2002) Signal transduction pathways activated by the IL-1 receptor/Toll-like receptor superfamily. Curr Top Microbiol Immunol 270:47–61PubMed
18.
Zurück zum Zitat Courts C, Montesinos-Rongen M, Martin-Subero JI, Brunn A, Siemer D, Zuhlke-Jenisch R, Pels H, Jurgens A, Schlegel U, Schmidt-Wolf IG, Schaller C, Reifenberger G, Sabel M, Warnecke-Eberz U, Wiestler OD, Kuppers R, Siebert R, Deckert M (2007) Transcriptional profiling of the nuclear factor-kappaB pathway identifies a subgroup of primary lymphoma of the central nervous system with low BCL10 expression. J Neuropathol Exp Neurol 66:230–237. doi:10.1097/01.jnen.0000248553.45456.96 PubMedCrossRef Courts C, Montesinos-Rongen M, Martin-Subero JI, Brunn A, Siemer D, Zuhlke-Jenisch R, Pels H, Jurgens A, Schlegel U, Schmidt-Wolf IG, Schaller C, Reifenberger G, Sabel M, Warnecke-Eberz U, Wiestler OD, Kuppers R, Siebert R, Deckert M (2007) Transcriptional profiling of the nuclear factor-kappaB pathway identifies a subgroup of primary lymphoma of the central nervous system with low BCL10 expression. J Neuropathol Exp Neurol 66:230–237. doi:10.​1097/​01.​jnen.​0000248553.​45456.​96 PubMedCrossRef
19.
Zurück zum Zitat Wolska A, Lech-Maranda E, Robak T (2009) Toll-like receptors and their role in hematologic malignancies. Curr Mol Med 9:324–335PubMedCrossRef Wolska A, Lech-Maranda E, Robak T (2009) Toll-like receptors and their role in hematologic malignancies. Curr Mol Med 9:324–335PubMedCrossRef
20.
Zurück zum Zitat Zhao WJ, Xi LY, Ma L (2008) Effect of Penicillium marneffei on TLR-2, TLR-4, and Dectin-1 expression and TNF-alpha production in macrophage. Nan Fang Yi Ke Da Xue Xue Bao 28:37–40PubMed Zhao WJ, Xi LY, Ma L (2008) Effect of Penicillium marneffei on TLR-2, TLR-4, and Dectin-1 expression and TNF-alpha production in macrophage. Nan Fang Yi Ke Da Xue Xue Bao 28:37–40PubMed
26.
Zurück zum Zitat Gonzalez-Aguilar A, Idbaih A, Boisselier B, Habbita N, Rossetto M, Laurenge A, Bruno A, Jouvet A, Polivka M, Adam C, Figarella-Branger D, Miquel C, Vital A, Ghesquieres H, Gressin R, Delwail V, Taillandier L, Chinot O, Soubeyran P, Gyan E, Choquet S, Houillier C, Soussain C, Tanguy ML, Marie Y, Mokhtari K, Hoang-Xuan K (2012) Recurrent mutations of MYD88 and TBL1XR1 in primary central nervous system lymphomas. Clin Cancer Res Off J Am Assoc Cancer Res 18:5203–5211. doi:10.1158/1078-0432.ccr-12-0845 CrossRef Gonzalez-Aguilar A, Idbaih A, Boisselier B, Habbita N, Rossetto M, Laurenge A, Bruno A, Jouvet A, Polivka M, Adam C, Figarella-Branger D, Miquel C, Vital A, Ghesquieres H, Gressin R, Delwail V, Taillandier L, Chinot O, Soubeyran P, Gyan E, Choquet S, Houillier C, Soussain C, Tanguy ML, Marie Y, Mokhtari K, Hoang-Xuan K (2012) Recurrent mutations of MYD88 and TBL1XR1 in primary central nervous system lymphomas. Clin Cancer Res Off J Am Assoc Cancer Res 18:5203–5211. doi:10.​1158/​1078-0432.​ccr-12-0845 CrossRef
27.
Zurück zum Zitat Decker T, Schneller F, Kronschnabl M, Dechow T, Lipford GB, Wagner H, Peschel C (2000) Immunostimulatory CpG-oligonucleotides induce functional high affinity IL-2 receptors on B-CLL cells: costimulation with IL-2 results in a highly immunogenic phenotype. Exp Hematol 28:558–568PubMedCrossRef Decker T, Schneller F, Kronschnabl M, Dechow T, Lipford GB, Wagner H, Peschel C (2000) Immunostimulatory CpG-oligonucleotides induce functional high affinity IL-2 receptors on B-CLL cells: costimulation with IL-2 results in a highly immunogenic phenotype. Exp Hematol 28:558–568PubMedCrossRef
28.
Zurück zum Zitat Jahrsdorfer B, Muhlenhoff L, Blackwell SE, Wagner M, Poeck H, Hartmann E, Jox R, Giese T, Emmerich B, Endres S, Weiner GJ, Hartmann G (2005) B-cell lymphomas differ in their responsiveness to CpG oligodeoxynucleotides. Clin Cancer Res Off J Am Assoc Cancer Res 11:1490–1499. doi:10.1158/1078-0432.CCR-04-1890 CrossRef Jahrsdorfer B, Muhlenhoff L, Blackwell SE, Wagner M, Poeck H, Hartmann E, Jox R, Giese T, Emmerich B, Endres S, Weiner GJ, Hartmann G (2005) B-cell lymphomas differ in their responsiveness to CpG oligodeoxynucleotides. Clin Cancer Res Off J Am Assoc Cancer Res 11:1490–1499. doi:10.​1158/​1078-0432.​CCR-04-1890 CrossRef
30.
Zurück zum Zitat Ben Abdelwahed R, Cosette J, Donnou S, Crozet L, Ouakrim H, Fridman WH, Sautes-Fridman C, Mahjoub A, Fisson S (2013) Lymphoma B-cell responsiveness to CpG-DNA depends on the tumor microenvironment. J Exp Clin Cancer Res CR 32:18. doi:10.1186/1756-9966-32-18 CrossRef Ben Abdelwahed R, Cosette J, Donnou S, Crozet L, Ouakrim H, Fridman WH, Sautes-Fridman C, Mahjoub A, Fisson S (2013) Lymphoma B-cell responsiveness to CpG-DNA depends on the tumor microenvironment. J Exp Clin Cancer Res CR 32:18. doi:10.​1186/​1756-9966-32-18 CrossRef
31.
Zurück zum Zitat Kraan W, van Keimpema M, Horlings HM, Schilder-Tol EJ, Oud ME, Noorduyn LA, Kluin PM, Kersten MJ, Spaargaren M, Pals ST (2014) High prevalence of oncogenic MYD88 and CD79B mutations in primary testicular diffuse large B-cell lymphoma. Leukemia 28:719–720. doi:10.1038/leu.2013.348 PubMedCrossRef Kraan W, van Keimpema M, Horlings HM, Schilder-Tol EJ, Oud ME, Noorduyn LA, Kluin PM, Kersten MJ, Spaargaren M, Pals ST (2014) High prevalence of oncogenic MYD88 and CD79B mutations in primary testicular diffuse large B-cell lymphoma. Leukemia 28:719–720. doi:10.​1038/​leu.​2013.​348 PubMedCrossRef
32.
Zurück zum Zitat Brunn A, Utermohlen O, Sanchez-Ruiz M, Montesinos-Rongen M, Blau T, Schluter D, Deckert M (2010) Dual role of B cells with accelerated onset but reduced disease activity in P0(1)(0)(6)(-)(1)(2)(5)-induced experimental autoimmune neuritis of IgH (0)(/)(0) mice. Acta Neuropathol 120:667–681. doi:10.1007/s00401-010-0724-8 PubMedCrossRef Brunn A, Utermohlen O, Sanchez-Ruiz M, Montesinos-Rongen M, Blau T, Schluter D, Deckert M (2010) Dual role of B cells with accelerated onset but reduced disease activity in P0(1)(0)(6)(-)(1)(2)(5)-induced experimental autoimmune neuritis of IgH (0)(/)(0) mice. Acta Neuropathol 120:667–681. doi:10.​1007/​s00401-010-0724-8 PubMedCrossRef
33.
Zurück zum Zitat Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB, Kohlhammer H, Lamy L, Zhao H, Yang Y, Xu W, Shaffer AL, Wright G, Xiao W, Powell J, Jiang JK, Thomas CJ, Rosenwald A, Ott G, Muller-Hermelink HK, Gascoyne RD, Connors JM, Johnson NA, Rimsza LM, Campo E, Jaffe ES, Wilson WH, Delabie J, Smeland EB, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Pierce SK, Staudt LM (2010) Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463:88–92. doi:10.1038/nature08638 PubMedCentralPubMedCrossRef Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB, Kohlhammer H, Lamy L, Zhao H, Yang Y, Xu W, Shaffer AL, Wright G, Xiao W, Powell J, Jiang JK, Thomas CJ, Rosenwald A, Ott G, Muller-Hermelink HK, Gascoyne RD, Connors JM, Johnson NA, Rimsza LM, Campo E, Jaffe ES, Wilson WH, Delabie J, Smeland EB, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Pierce SK, Staudt LM (2010) Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463:88–92. doi:10.​1038/​nature08638 PubMedCentralPubMedCrossRef
34.
Zurück zum Zitat Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH, Kohlhammer H, Xu W, Yang Y, Zhao H, Shaffer AL, Romesser P, Wright G, Powell J, Rosenwald A, Muller-Hermelink HK, Ott G, Gascoyne RD, Connors JM, Rimsza LM, Campo E, Jaffe ES, Delabie J, Smeland EB, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Staudt LM (2011) Oncogenically active MYD88 mutations in human lymphoma. Nature 470:115–119. doi:10.1038/nature09671 PubMedCrossRef Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH, Kohlhammer H, Xu W, Yang Y, Zhao H, Shaffer AL, Romesser P, Wright G, Powell J, Rosenwald A, Muller-Hermelink HK, Ott G, Gascoyne RD, Connors JM, Rimsza LM, Campo E, Jaffe ES, Delabie J, Smeland EB, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Staudt LM (2011) Oncogenically active MYD88 mutations in human lymphoma. Nature 470:115–119. doi:10.​1038/​nature09671 PubMedCrossRef
36.
Zurück zum Zitat Ye H, Gong L, Liu H, Hamoudi RA, Shirali S, Ho L, Chott A, Streubel B, Siebert R, Gesk S, Martin-Subero JI, Radford JA, Banerjee S, Nicholson AG, Ranaldi R, Remstein ED, Gao Z, Zheng J, Isaacson PG, Dogan A, Du MQ (2005) MALT lymphoma with t(14;18)(q32;q21)/IGH-MALT1 is characterized by strong cytoplasmic MALT1 and BCL10 expression. J Pathol 205:293–301. doi:10.1002/path.1715 PubMedCrossRef Ye H, Gong L, Liu H, Hamoudi RA, Shirali S, Ho L, Chott A, Streubel B, Siebert R, Gesk S, Martin-Subero JI, Radford JA, Banerjee S, Nicholson AG, Ranaldi R, Remstein ED, Gao Z, Zheng J, Isaacson PG, Dogan A, Du MQ (2005) MALT lymphoma with t(14;18)(q32;q21)/IGH-MALT1 is characterized by strong cytoplasmic MALT1 and BCL10 expression. J Pathol 205:293–301. doi:10.​1002/​path.​1715 PubMedCrossRef
37.
Zurück zum Zitat Schwindt H, Vater I, Kreuz M, Montesinos-Rongen M, Brunn A, Richter J, Gesk S, Ammerpohl O, Wiestler OD, Hasenclever D, Deckert M, Siebert R (2009) Chromosomal imbalances and partial uniparental disomies in primary central nervous system lymphoma. Leukemia 23:1875–1884. doi:10.1038/leu.2009.120 PubMedCrossRef Schwindt H, Vater I, Kreuz M, Montesinos-Rongen M, Brunn A, Richter J, Gesk S, Ammerpohl O, Wiestler OD, Hasenclever D, Deckert M, Siebert R (2009) Chromosomal imbalances and partial uniparental disomies in primary central nervous system lymphoma. Leukemia 23:1875–1884. doi:10.​1038/​leu.​2009.​120 PubMedCrossRef
Metadaten
Titel
Differential expression of Toll-like receptor (TLR) and B cell receptor (BCR) signaling molecules in primary diffuse large B-cell lymphoma of the central nervous system
verfasst von
Ariz Akhter
Noraidah Masir
Ghaleb Elyamany
Kean-Chang Phang
Etienne Mahe
Ali Matar Al-Zahrani
Meer-Taher Shabani-Rad
Douglas Allan Stewart
Adnan Mansoor
Publikationsdatum
01.01.2015
Verlag
Springer US
Erschienen in
Journal of Neuro-Oncology / Ausgabe 2/2015
Print ISSN: 0167-594X
Elektronische ISSN: 1573-7373
DOI
https://doi.org/10.1007/s11060-014-1655-3

Weitere Artikel der Ausgabe 2/2015

Journal of Neuro-Oncology 2/2015 Zur Ausgabe

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Neu im Fachgebiet Neurologie

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.