The role of IrF-4 and IRF-8 in the Pathogenesis of B-cell neoplasm

IRF-4和IRF-8是IRF家族的转录因子，在B淋巴细胞的发育过程中起重要作用。IRF-4的表达被认为是弥漫性大B细胞淋巴瘤（DL）的预后因素之一。另一方面，IRF-8的缺乏诱导骨髓性白血病。本研究的目的是探讨这些分子是否在B细胞恶性肿瘤的发病机制中起作用。首先，采用半定量RT-PCR检测IRF-4和IRF-8的表达。分析了42例DL和32例滤泡性淋巴瘤（FL）肿瘤。在大多数样本中同时检测到IRF-4和IRF-8基因。在13例DL样本（30.9%）和16例FL样本（69.5%）中观察到IRF-8表达高于IRF-4。有趣的是，IRF-4<IRF-8患者的总生存率更好（统计学上不显著）。这些结果表明，DL可以根据这些因素的表达进行分类。接下来，为了鉴定单个肿瘤细胞中这些因子目录的蛋白，免疫组织化学进行了挑战。然而，由于缺乏针对人IRF-8的良好抗体，因此无法获得明确的结果。近年来，研究发现IRF-4和IRF-8与bc 1 -2在恶性血液病的发病过程中有协同作用。Bcl-2是一种凋亡因子，与IgH形成嵌合体基因，通常在FL中发现易位（14; 8）。为了阐明这种易位在DL中的作用，对35例高危DL患者的样本进行了bcl 2/IgH的FISH和bcl 1 -2蛋白的免疫组化。在死亡病例标本中，Bc 12/IgH融合阳性率为57.1%。另一方面，在71.4%的幸存者肿瘤细胞中均未检测到bc 1 - 2/IgH融合和bc 1 -2表达，表明易位（14; 18）在难治性DL中发挥关键作用。

IRF-4 and IRF-8 are the transcription factors of IRF family playing the important role in the development of B-lymphocytes. The expression of IRF-4 has been recognized as one of the prognostic factor for diffuse large B-cell lymphoma (DL). On the other hands, the lack of IRF-8 induces myeloid leukemia. The aim of this study is to approach the question if these molecules act in the pathogenesis of B-cell malignancies. First of all, the expression of IRF-4 and IRF-8 was tested by semi-quantitative RT-PCR. Forty-two DL and 32 follicular lymphoma (FL) tumors were analyzed. Both IRF-4 and IRF-8 gene were detected in most samples. Higher IRF-8 expression than IRF-4 was seen in 13 DL samples (30.9%) and 16 in FL samples (69.5%). Interestingly, the overall survival was better in IRF-4<IRF-8 patients (statistically not significant). These results suggests that DL could be categorized based on the expression of these factors. Next, to identify protein of these factors directory in single tumor cell, immunohistochemistry was challenged. However, it was unable to gain the clear results because of the lack of good antibody for human IRF-8. Recently, IRF-4 and 8 are reported to cooperate with bc1-2 during the pathogenesis of hematological malignancies. Bcl-2 is an apoptotic factor forming chimera gene with IgH resulted by the translocation (14; 8) typically found in FL. Also, this protein is over expressed in high risk DL cells. To clarify the role of this translocation in DL, FISH for bcl2/IgH, as well as immunohistochemistry for bc1-2 protein were performed on 35 samples from high risk DL patients. Bc12/IgH fusion was detected in 57.1% of samples from dead cases. On the other hands, neither bc12/IgH fusion and bc1-2 expression was detected in 71.4% of tumor cells from survivors, suggesting that translocation (14; 18) plays key role in refractory DL.