Multiple Myeloma Oncogene 1 (MUM1)/Interferon Regulatory Factor 4 (IRF4) Upregulates Monokine Induced by Interferon-gamma (MIG) Gene Expression in B-Cell Malignancy.
Multiple Myeloma Oncogene 1 (MUM1)/Interferon Regulatory Factor 4 (IRF4) Upregulates Monokine Induced by Interferon-gamma (MIG) Gene Expression in B-Cell Malignancy.
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DOI：
10.1182/blood.v104.11.1111.1111
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发表时间：
2004-11
期刊：
影响因子：
20.3
通讯作者：
S. Iida;M. Uranishi;T. Sanda;T. Ishida;E. Tajima;Masato Ito;H. Komatsu;H. Inagaki;R. Ueda
中科院分区：
文献类型：
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作者：
S. Iida;M. Uranishi;T. Sanda;T. Ishida;E. Tajima;Masato Ito;H. Komatsu;H. Inagaki;R. Ueda
MUM1(multiple myeloma oncogene 1)/IRF4（interferon regulatory factor 4）是多发性骨髓瘤中由于t(6;14)（p25;q32）而激活的转录调节因子。MUM1表达见于各种b细胞淋巴瘤/白血病，据报道，在一些淋巴瘤亚型中，包括弥漫性大b细胞淋巴瘤（DLBCL）和b细胞慢性淋巴细胞白血病（B-CLL）， MUM1表达预示着不利的结果。为了阐明其在b细胞恶性肿瘤中的作用，我们制备了稳定表达MUM1的Ba/F3细胞，其增殖速度高于亲本细胞，并进行了cDNA微阵列分析，以鉴定受MUM1表达调控的基因。我们发现，在表达mum1的细胞中，fk506结合蛋白3 （FKBP3）、干扰素诱导的单因子（MIG）、Fas凋亡抑制分子（Faim）和锌指蛋白94等4个基因的表达发生了改变。随后，我们重点研究了MIG，因为在诱导型MUM1表达系统中，它的表达会被MUM1立即上调。在报告子实验中，MUM1与PU.1合作激活了MIG启动子序列，并且在染色质免疫沉淀实验中证实了MUM1与MIG启动子序列之间的相互作用。在B-CLL细胞系中，MIG的表达与MUM1的表达相关，其受体CXCR3也在MUM1阳性的B-CLL细胞系中共表达。有趣的是，用针对MIG及其受体CXCR3的中和抗体治疗，部分抑制了两种表达mum1的B-CLL细胞系的增殖。这些结果表明，MUM1通过调节包括MIG在内的多种基因的表达，在b细胞淋巴瘤/白血病的进展中发挥一定的作用。
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.