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Disruption of the B-cell specific transcriptional program in HHV-8 associated primary effusion lymphoma cell lines

机译：HHV-8相关原发性淋巴瘤细胞系中B细胞特异性转录程序的破坏

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Primary effusion lymphoma (PEL) is a lymphoproliferative disease of B-cell origin that is associated with HHV-8 infection. PEL cells harbor a non-B, non-T phenotype and lack significant surface immunoglobulin (Ig) expression, a characteristic that has not been fully explained. In the present study, we demonstrate that PEL cells constitutively express interferon regulatory factor (IRF)-4, a transcription factor that regulates the activity of the immunoglobulin light-chain enhancer elements B and E3' through binding to a composite Ets-IRF site. IRF-4 activity requires its physical interaction with PU.1, an Ets family member involved in the activation of genes essential for B-cell development. However, in PEL-derived B-cell lines, PU.1 expression was completely abrogated; expression of the B cell specific transcription factor Oct-2, which is known to regulate PU.1 expression, was also abolished. Moreover, the B-cell-specific coactivator of octamer factors, BOB-1/OcaB, was expressed at very decreased levels in PEL cells. Ectopic expression of Oct-2 was able to fully restore PU.1 promoter activity in the PEL cell line BCBL-1, while PU.1 expression also reconstituted the activity of the B Ets-IRF site. In addition, protein levels of BSAP/Pax-5 and IRF-8/ICSBP were undetectable in PEL cells. The pattern of transcription factor ablation observed in PEL was found to be comparable to that observed in classical Hodgkin's disease-derived cell lines, which also lack B-cell-specific surface markers. These observations indicate that disruption of the B-cell-specific transcriptional program is likely to contribute to the incomplete B-cell phenotype characteristic of PEL cells.
机译：原发性渗出性淋巴瘤（PEL）是B细胞起源的淋巴增生性疾病，与HHV-8感染相关。 PEL细胞具有非B，非T表型，并且缺乏明显的表面免疫球蛋白（Ig）表达，这一特征尚未得到充分解释。在本研究中，我们证明PEL细胞组成性表达干扰素调节因子（IRF）-4，该转录因子通过与复合Ets-IRF位点结合来调节免疫球蛋白轻链增强子元件B和E3'的活性。 IRF-4活性需要与PU.1物理相互作用，PU.1是Ets家族成员，参与激活B细胞发育所必需的基因。但是，在PEL衍生的B细胞系中，PU.1的表达被完全废除。还取消了B细胞特异性转录因子Oct-2的表达，后者已知可调节PU.1的表达。此外，八聚体因子的B细胞特异性共激活因子BOB-1 / OcaB在PEL细胞中以非常低的水平表达。 Oct-2的异位表达能够完全恢复PEL细胞系BCBL-1中PU.1启动子的活性，而PU.1表达也可以重建B Ets-IRF位点的活性。此外，在PEL细胞中无法检测到BSAP / Pax-5和IRF-8 / ICSBP的蛋白质水平。发现在PEL中观察到的转录因子消融模式与在经典霍奇金氏病衍生细胞系中观察到的模式相当，后者也缺乏B细胞特异性表面标记。这些观察表明，B细胞特异性转录程序的破坏很可能导致PEL细胞的B细胞表型特征不完整。

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