2005 Fiscal Year Final Research Report Summary
Identification of the downstream target genes regulated by MUM1/IRF4 and its application for the novel molecular targeting therapy in lymphoid malignancies
| Project/Area Number |
16590953
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | NAGOYA CITY UNIVERSITY |
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Principal Investigator |
IIDA Shinsuke Nagoya City University, Graduate School of Medical Sciences, Assistant Professor, 大学院・医学研究科, 講師 (50295614)
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| Project Period (FY) |
2004 – 2005
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| Keywords | MUM1 / IRF4 / lymphoid makignancies / transcriptional regulation genes / molecular targeting therapy / MIG / CXCR3 / B-CLL / DLBCL |
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| Research Abstract |
MUM1(multiple myeloma oncogene 1)/IRF4(interferon regulatory factor 4) is a transcription factor that is activated as a result of t(6;14)(p25;q32) in multiple myeloma. MUM1 expression is seen in various B-cell lymphomas and predicts an unfavorable outcome in some lymphoma subtypes. To elucidate its role in B-cell malignancies, we prepared MUM1-expressing Ba/F3 cells, which proliferated at a higher rate than the parental cells, and performed cDNA microarray analysis to identify genes whose expression is regulated by MUM1. We found that the expression of four genes including FK506-binding protein 3(FKBP3), the Monokine induced by interferon-g(MIG), Fas apoptotic inhibitory molecule(Faim) and Zinc finger protein 94 was altered in the MUM1-expressing cells. We then focused on MIG since its expression was immediately upregulated by MUM1. In reporter assays, MUM1 activated the MIG promoter in cooperation with PU.1, and the interaction between MUM1 and the MIG promoter sequence was confirmed. The expression of MIG was correlated with that of MUM1 in B-CLL cell lines, and treatment with neutralizing antibodies against MIG and its receptor, CXCR3, partially inhibited the proliferation of two MUM1-expressing lines. These results suggest that MUM1 plays roles in the progression of B-cell lymphoma/leukemia by regulating the expression of various genes including MIG. The MIG expression in the diffuse large B-cell lymphoma-derived cell lines was also seen in those expressing highly amount of the MUM1. We then used Affymetrix GeneChip assay to search for differentially expressed genes in between a Burkitt's lymphoma-derived cell line, P3HR-1 transfected with MUM1 and that transfected with empty vector alone. We have so far identified forty-four upregulated and twenty-two downregulated genes in MUM1-expressing cells, which are being explored for their roles in B-cell tumorigenesis.
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[Journal Article] Ark5 is transcriptionally regulated by the large-Maf family and mediates IGF-1-induced cell invasion in multiple myeloma : Ark5 as a new molecular determinant of malignant multiple myeloma.2005
Author(s)
Suzuki A, Iida S, Kato-Uranishi M, Tajima E, Zhan F, Hanamura I, Huang Y, Ogura T, Takahashi S, Ueda R, Barlogie B, Shaughnessy J, Esumi H.
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Journal Title
Oncogene 24(46)
Pages: 6936-6944
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Reduced-intensity conditioning allogeneic stem cell transplantation for multiple myeloma : results from the Japan myeloma study group.2005
Author(s)
Shimazaki C, Fujii H, Yoshida T, Chou T, Nishimura M, Asaoku H, Miyawaki S, Ishii A, Ishida T, Taniwaki M, Iida S, Takagi T, Takatsuki K.
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Journal Title
Int J Hematol 81
Pages: 342-348
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin.2004
Author(s)
Ding J, Komatsu H, Wakita A, Kato-Uranishi M, Ito M, Satoh A, Tsuboi K, Nitta M, Miyazaki H, Iida S, Ueda R.
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Journal Title
Blood 103
Pages: 4198-4200
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Molecular-cytogenetic characterization of non-Hodgkin's lymphoma with double and cryptic translocations of the immunoglobulin heavy chain gene.2004
Author(s)
Kanda-Akano Y, Nomura K, Fujita Y, Horiike S, Nishida K, Nagai M, Miura I, Nakamura S, Seto M, Iida S, Ueda R, Taniwaki M.
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Journal Title
Leuk Lymphoma 45
Pages: 1559-1567
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The CC chemoine receptor(CCR)4 as a novel molecular target for immunotherapy in adult T-cell leukemia/lymphoma.2004
Author(s)
Ishida T, Iida S, Akatsuka Y, Ishii T, Miyazaki M, Komatsu H, Inagaki H, Okada N, Fujita T, Shitara K, Akinaga S, Takahashi T, Utsunomiya A, Ueda R.
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Journal Title
Clin Cancer Res 10
Pages: 7529-7539
Description
「研究成果報告書概要(欧文)」より
