Multiple myeloma (MM), a progressive hematological neoplasm, is thought to result from multiple genetic events affecting the terminal plasma cell. However, genetic aberrations related to MM are seldom reported. Using our in-house array-based comparative genomic hybridization system to locate candidate target genes with following their expression analysis, we identified POU2AF1 at 11q23.1 as a probable amplification target in MM cell lines. POU2AF1 is a B-cell-specific transcriptional co-activator, which interacts with octamer-binding transcription factors Oct-1 and Oct-2, and augments their function. Downregulation of POU2AF1 expression by specific small-interfering RNA (siRNA) inhibited MM cell growth, whereas ectopic expression of POU2AF1 promoted growth of MM cells. Among putative transcriptional targets for POU2AF1, B-cell maturation factor, TNFRSF17, enhanced its transcription by POU2AF1, and POU2AF1 directly bound to an octamer site within the 5′ region of TNFRSF17. Expression level of TNFRSF17 was closely correlated with that of POU2AF1 in cell lines and primary samples of MM, and decreasing TNFRSF17 expression by means of TNFRSF17 siRNA inhibited MM cell growth. Taken together, our results suggest that POU2AF1, when activated by amplification or other mechanisms, may contribute to progression of MM by accelerating growth of MM cells through direct transactivation of one of its target genes, TNFRSF17.
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Brunner C, Marinkovic D, Klein J, Samardzic T, Nitschke L, Wirth T . (2003). B cell-specific transgenic expression of Bcl2 rescues early B lymphopoiesis but not B cell responses in BOB.1/OBF.1-deficient mice. J Exp Med 197: 1205–1211.
Carrasco DR, Tonon G, Huang Y, Zhang Y, Sinha R, Feng B et al. (2006). High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell 9: 313–325.
Cepek KL, Chasman DI, Sharp PA . (1996). Sequence-specific DNA binding of the B-cell-specific coactivator OCA-B. Genes Dev 10: 2079–2088.
Cigudosa JC, Rao PH, Calasanz MJ, Odero MD, Michaeli J, Jhanwar SC et al. (1998). Characterization of nonrandom chromosomal gains and losses in multiple myeloma by comparative genomic hybridization. Blood 91: 3007–3010.
Claudio JO, Masih-Khan E, Tang H, Goncalves J, Voralia M, Li ZH et al. (2002). A molecular compendium of genes expressed in multiple myeloma. Blood 100: 2175–2186.
Cremer FW, Bila J, Buck I, Kartal M, Hose D, Ittrich C et al. (2005a). Delineation of distinct subgroups of multiple myeloma and a model for clonal evolution based on interphase cytogenetics. Genes Chromosomes Cancer 44: 194–203.
Cremer FW, Kartal M, Hose D, Bila J, Buck I, Bellos F et al. (2005b). High incidence and intraclonal heterogeneity of chromosome 11 aberrations in patients with newly diagnosed multiple myeloma detected by multiprobe interphase FISH. Cancer Genet Cytogenet 161: 116–124.
Fonseca R, Bailey RJ, Ahmann GJ, Rajkumar SV, Hoyer JD, Lust JA et al. (2002). Genomic abnormalities in monoclonal gammopathy of undetermined significance. Blood 100: 1417–1424.
Fonseca R, Barlogie B, Bataille R, Bastard C, Bergsagel PL, Chesi M et al. (2004). Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res 64: 1546–1558.
Gonzalez MB, Hernandez JM, Garcia JL, Lumbreras E, Castellanos M, Hernandez JM et al. (2004). The value of fluorescence in situ hybridization for the detection of 11q in multiple myeloma. Haematologica 89: 1213–1218.
Greiner A, Muller KB, Hess J, Pfeffer K, Muller-Hermelink HK, Wirth T . (2000). Up-regulation of BOB.1/OBF.1 expression in normal germinal center B cells and germinal center-derived lymphomas. Am J Pathol 156: 501–507.
Gstaiger M, Georgiev O, van Leeuwen H, van der Vliet P, Schaffner W . (1996). The B cell coactivator Bob1 shows DNA sequence-dependent complex formation with Oct-1/Oct-2 factors, leading to differential promoter activation. EMBO J 15: 2781–2790.
Gutierrez NC, Hernandez JM, Garcia JL, Canizo MC, Gonzalez M, Hernandez J et al. (2001). Differences in genetic changes between multiple myeloma and plasma cell leukemia demonstrated by comparative genomic hybridization. Leukemia 15: 840–845.
Hatzoglou A, Roussel J, Bourgeade MF, Rogier E, Madry C, Inoue J et al. (2000). TNF receptor family member BCMA (B cell maturation) associates with TNF receptor-associated factor (TRAF) 1, TRAF2, and TRAF3 and activates NF-kappa B, elk-1, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. J Immunol 165: 1322–1330.
Heckman CA, Duan H, Garcia PB, Boxer LM . (2006). Oct transcription factors mediate t(14;18) lymphoma cell survival by directly regulating bcl-2 expression. Oncogene 25: 888–898.
Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC . (2004). Advances in biology of multiple myeloma: clinical applications. Blood 104: 607–618.
Hoechtlen-Vollmar W, Menzel G, Bartl R, Lamerz R, Wick M, Seidel D . (2000). Amplification of cyclin D1 gene in multiple myeloma: clinical and prognostic relevance. Br J Haematol 109: 30–38.
Husson H, Carideo EG, Neuberg D, Schultze J, Munoz O, Marks PW et al. (2002). Gene expression profiling of follicular lymphoma and normal germinal center B cells using cDNA arrays. Blood 99: 282–289.
Inazawa J, Inoue J, Imoto I . (2004). Comparative genomic hybridization (CGH)-arrays pave the way for identification of novel cancer-related genes. Cancer Sci 95: 559–563.
Inoue J, Otsuki T, Hirasawa A, Imoto I, Matsuo Y, Shimizu S et al. (2004). Overexpression of PDZK1 within the 1q12–q22 amplicon is likely to be associated with drug-resistance phenotype in multiple myeloma. Am J Pathol 165: 71–81.
Kabat D . (1972). Gene selection in hemoglobin and in antibody-synthesizing cells. Science 175: 134–140.
Kim U, Qin XF, Gong S, Stevens S, Luo Y, Nussenzweig M et al. (1996). The B-cell-specific transcription coactivator OCA-B/OBF-1/Bob-1 is essential for normal production of immunoglobulin isotypes. Nature 383: 542–547.
Kim U, Siegel R, Ren X, Gunther CS, Gaasterland T, Roeder RG . (2003). Identification of transcription coactivator OCA-B-dependent genes involved in antigen-dependent B cell differentiation by cDNA array analyses. Proc Natl Acad Sci USA 100: 8868–8873.
Kuehl WM, Bergsagel PL . (2002). Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer 2: 175–187.
Ladanyi M, Wang S, Niesvizky R, Feiner H, Michaeli J . (1992). Proto-oncogene analysis in multiple myeloma. Am J Pathol 141: 949–953.
Largo C, Alvarez S, Saez B, Blesa D, Martin-Subero JI, Gonzalez-Garcia I et al. (2006). Identification of overexpressed genes in frequently gained/amplified chromosome regions in multiple myeloma. Haematologica 91: 184–191.
Lins K, Remenyi A, Tomilin A, Massa S, Wilmanns M, Matthias P et al. (2003). OBF1 enhances transcriptional potential of Oct1. EMBO J 22: 2188–2198.
Luo Y, Fujii H, Gerster T, Roeder RG . (1992). A novel B cell-derived coactivator potentiates the activation of immunoglobulin promoters by octamer-binding transcription factors. Cell 71: 231–241.
Luo Y, Roeder RG . (1995). Cloning, functional characterization, and mechanism of action of the B-cell-specific transcriptional coactivator OCA-B. Mol Cell Biol 15: 4115–4124.
Miura K, Iida S, Hanamura I, Kato M, Banno S, Ishida T et al. (2003). Frequent occurrence of CCND1 deregulation in patients with early stages of plasma cell dyscrasia. Cancer Sci 94: 350–354.
Moreau LA, McGrady P, London WB, Shimada H, Cohn SL, Maris JM et al. (2006). Does MYCN amplification manifested as homogeneously staining regions at diagnosis predict a worse outcome in children with neuroblastoma? A Children's Oncology Group study. Clin Cancer Res 12: 5693–5697.
Nielsen PJ, Georgiev O, Lorenz B, Schaffner W . (1996). B lymphocytes are impaired in mice lacking the transcriptional co-activator Bob1/OCA-B/OBF1. Eur J Immunol 26: 3214–3218.
Novak AJ, Darce JR, Arendt BK, Harder B, Henderson K, Kindsvogel W et al. (2004). Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood 103: 689–694.
Robetorye RS, Bohling SD, Morgan JW, Fillmore GC, Lim MS, Elenitoba-Johnson KS . (2002). Microarray analysis of B-cell lymphoma cell lines with the t(14;18). Mol Diagn 4: 123–136.
Samardzic T, Marinkovic D, Nielsen PJ, Nitschke L, Wirth T . (2002). BOB.1/OBF.1 deficiency affects marginal-zone B-cell compartment. Mol Cell Biol 22: 8320–8331.
Schneider P, MacKay F, Steiner V, Hofmann K, Bodmer JL, Holler N et al. (1999). BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med 189: 1747–1756.
Schubart DB, Rolink A, Kosco-Vilbois MH, Botteri F, Matthias P . (1996). B-cell-specific coactivator OBF-1/OCA-B/Bob1 required for immune response and germinal centre formation. Nature 383: 538–542.
Schubart K, Massa S, Schubart D, Corcoran LM, Rolink AG, Matthias P . (2001). B cell development and immunoglobulin gene transcription in the absence of Oct-2 and OBF-1. Nat Immunol 2: 69–74.
Seidl S, Kaufmann H, Drach J . (2003). New insights into the pathophysiology of multiple myeloma. Lancet Oncol 4: 557–564.
Sonoda I, Imoto I, Inoue J, Shibata T, Shimada Y, Chin K et al. (2004). Frequent silencing of low density lipoprotein receptor-related protein 1B (LRP1B) expression by genetic and epigenetic mechanisms in esophageal squamous cell carcinoma. Cancer Res 64: 3741–3747.
Sonoki T, Nakazawa N, Hata H, Taniwaki M, Nagasaki A, Seto M et al. (1998). Amplification and overexpression of the PRAD1/Cyclin D1 gene in a multiple myeloma cell line. Int J Hematol 68: 459–461.
Standal T, Hjorth-Hansen H, Rasmussen T, Dahl IM, Lenhoff S, Brenne AT et al. (2004). Osteopontin is an adhesive factor for myeloma cells and is found in increased levels in plasma from patients with multiple myeloma. Haematologica 89: 174–182.
Takada H, Imoto I, Tsuda H, Sonoda I, Ichikura T, Mochizuki H et al. (2005). Screening of DNA copy-number aberrations in gastric cancer cell lines by array-based comparative genomic hybridization. Cancer Sci 96: 100–110.
Tanaka M, Herr W . (1990). Differential transcriptional activation by Oct-1 and Oct-2: interdependent activation domains induce Oct-2 phosphorylation. Cell 60: 375–386.
Teitell MA . (2003). OCA-B regulation of B-cell development and function. Trends Immunol 24: 546–553.
Tricot G, Barlogie B, Jagannath S, Bracy D, Mattox S, Vesole DH et al. (1995). Poor prognosis in multiple myeloma is associated only with partial or complete deletions of chromosome 13 or abnormalities involving 11q and not with other karyotype abnormalities. Blood 86: 4250–4256.
Yu X, Wang L, Luo Y, Roeder RG . (2001). Identification and characterization of a novel OCA-B isoform. Implications for a role in B cell signaling pathways. Immunity 14: 157–167.
Zwilling S, Dieckmann A, Pfisterer P, Angel P, Wirth T . (1997). Inducible expression and phosphorylation of coactivator BOB.1/OBF.1 in T cells. Science 277: 221–225.
This research was supported by grants-in-aid for Scientific Research and Scientific Research on Priority Areas (C), and a Center of Excellence Program for Research on Molecular Destruction and Reconstruction of Tooth and Bone from the Ministry of Education, Culture, Sports, Science, and Technology, Japan; and a grant from Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology Corporation (JST). We are grateful to Professor Yusuke Nakamura (Human Genome Center, Institute of Medical Science, The University of Tokyo) for continuous encouragement throughout this work, and Yoshinobu Matsuo (Hayashibara Biochemical Laboratories Incorporated, Okayama, Japan) for provision of cell lines. We also thank Chieko Hayashi, Ai Watanabe and Ayako Takahashi for their technical assistance.
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Zhao, C., Inoue, J., Imoto, I. et al. POU2AF1, an amplification target at 11q23, promotes growth of multiple myeloma cells by directly regulating expression of a B-cell maturation factor, TNFRSF17. Oncogene 27, 63–75 (2008). https://doi.org/10.1038/sj.onc.1210637
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