Multiple myeloma oncogene 1 (MUM1)/interferon regulatory factor 4 (IRF4) upregulates monokine induced by interferon-γ (MIG) gene expression in B-cell malignancy

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 until higher cellular density 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 interferonc(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, slightly 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.

Higher response to lenalidomide in relapsed/refractory diffuse large B‐cell lymphoma in nongerminal center B‐cell–like than in germinal center B‐cell–like phenotype

“…IRF4/MUM1 in cooperation with PU-1 enhances the transcription of the monokine induced by interferon-gamma (MIG) gene. 31 MIG protein interacts with the chemokine receptor 3 and induces an autocrine proliferation signal in malignant B cells. 31 IRF4/MUM1 up-regulation of MIG might be mediated by NF-KB activity.…”

Characterization of the Promoter and the Transcriptional Regulation of theLipoxin A4 Receptor(FPR2/ALX) Gene in Human Monocytes and Macrophages

“…MatInspector located two putative binding sites for IRF4 and IRF7 within this region. These transcription factors have already been shown to induce transcription upon stimulation with IFNs (51,52). To investigate whether one or both of these transcription factor binding sites are necessary for the IFN-g response of the FPR2/ALX gene, their core binding sites were mutated on the shortest P1-414 luciferase construct (Supplemental Table II).…”

Proteome analyses of the growth inhibitory effects of NCH-51, a novel histone deacetylase inhibitor, on lymphoid malignant cells

“…A human acute T-cell leukemia cell line, Jurkat, ATL cell lines, MT-2, ATL-102 and ED-40515(À), chronic lymphocytic leukemia cell lines, MEC2 and MO1043, Burkitt's lymphoma cell lines, Raji and Daudi and multiple myeloma cell lines, U266, XG7, KM5, ILKM-2 and RPMI-8226 were used in this study as described previously. [20][21][22][23][24] For normal controls, peripheral blood mononuclear cells (PBMCs) were obtained from four independent healthy donors upon informed consent after the approval of Institutional Ethical Committee. All cells were cultured in RPMI-1640 medium, supplemented with 10% fetal bovine serum at 371C in a 5% CO 2 incubator.…”