Multiple Myeloma Oncogene 1 (MUM1)/Interferon Regulatory Factor 4 (IRF4) Upregulates Monokine Induced by Interferon-gamma (MIG) Gene Expression in B-Cell Malignancy

MUM1(multiple myeloma oncogene 1)/IRF4(interferon regulatory factor 4) is a transcription regulatory 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/leukemias and has been reported to predict an unfavorable outcome in some lymphoma subtypes including diffuse large B-cell lymphoma (DLBCL) and B-cell chronic lymphocytic leukemia (B-CLL). To elucidate its role in B-cell malignancies, we prepared stably 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-gamma (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 inducible MUM1 expressing system. 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 in chromatin immunoprecipitation assay. The expression of MIG was correlated with that of MUM1 in B-CLL cell lines, and its receptor CXCR3 was also coexpressed in B-CLL cell lines that were positive for MUM1. Interestingly, treatment with neutralizing antibodies against MIG and its receptor, CXCR3, partially inhibited the proliferation of two MUM1-expressing B-CLL cell lines. These results suggest that MUM1 plays certain roles in the progression of B-cell lymphomas/leukemias by regulating the expression of various genes including MIG.