| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
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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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