Alterations in CIITA constitute a common mechanism accounting for downregulation of MHC class II expression in diffuse large B-cell lymphoma (DLBCL)
Alterations in CIITA constitute a common mechanism accounting for downregulation of MHC class II expression in diffuse large B-cell lymphoma (DLBCL)
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DOI：
10.1016/j.exphem.2008.10.001
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发表时间：
2009-02-01
影响因子：
2.6
通讯作者：
Murphy, Shawn P.
中科院分区：
文献类型：
--
作者：
Cycon, Kell A.;Rimsza, Lisa M.;Murphy, Shawn P.
客观的。弥漫性大 B 细胞淋巴瘤 (DLBCL) 中主要组织相容性复合物 II 类 (MHC-II) 抗原表达的下调与患者生存率的显着下降有关。然而，DLBCL 中 MHC-II 表达降低的分子机制尚不清楚。因此，我们在已建立的 DLBCL 细胞系中检查了这些机制。材料和方法。通过流式细胞术检查人类白细胞抗原（HLA）-DR表面表达。通过逆转录酶聚合酶链式反应研究MHC-II基因和MHC-II转录激活剂类If反式激活剂(CIITA)和RFX的表达。通过 I 链反应检查 MHC-II 基因的完整性。利用稳定转染测定来重建 CIITA 表达。结果。在 DLBCL 细胞系中观察到细胞表面 HLA-DR 表达水平的显着变化。 OCI-Ly10 细胞由于 6 号染色体上 MHC-II 位点内的纯合缺失而缺乏 HLA-DR 和 HLA-DQ 表达。OCI-Ly3 细胞中 MHC-II β 链表达的失调下调会介导 MHC-II 表面表达的急剧减少。在 SUDHL-4 和 SUDHL-6 细胞中，MHC-II 基因的表达协同降低，并与 MHC-II 转录的主要调节因子 CIITA 的表达定量相关。 DB 细胞缺乏 CIITA 和所有 MHC-II 基因的表达。用CIITA表达载体稳定转染DB细胞导致MHC-II基因表达协同上调，这证明了CIITA缺乏与MHC-II损失之间的因果关系。结论。这些数据表明，DLBCL 中 MHC-II 表达下调是通过多种不同机制发生的。然而，CIITA 表达的减少似乎是最普遍的机制。 (C) 2009 ISEH - 血液学和干细胞学会。由爱思唯尔公司出版
Objective. Significant decreases in patient survival are associated with downregulation of major histocompatibility complex class II (MHC-II) antigen expression in diffuse large B-cell lymphoma (DLBCL). However, the molecular mechanisms responsible for decreased MHC-II expression in DLBCL are poorly defined. We therefore examined these mechanisms in established DLBCL cell lines.Materials and Methods. Human leukocyte antigen (HLA)-DR surface expression was examined by flow cytometry. Expression of the MHC-II genes and the MHC-II transcriptional activators class If transactivator (CIITA) and RFX was investigated by reverse transcriptase polymerase polymerase chain reaction. The integrity of the MHC-II genes was examined by I chain reaction. Stable transfection assays were utilized to reconstitute CIITA expression.Results. Dramatic variations in the levels of cell surface HLA-DR expression were observed on the DLBCL cell lines. OCI-Ly10 cells lack HLA-DR and HLA-DQ expression due to homozygous deletions within the MHC-II locus on chromosome 6. Dyscoordinate downregulation of MHC-II beta-chain expression in OCI-Ly3 cells mediates dramatic reductions of MHC-II surface expression. In SUDHL-4 and SUDHL-6 cells, expression of the MHC-II genes is coordinately reduced and quantitatively correlated with expression of the CIITA, the master regulator of MHC-II transcription. DB cells lack expression of CIITA and all of the MHC-II genes. Stable transfection of DB cells with CIITA expression vectors resulted in coordinate upregulation of MHC-II gene expression, which demonstrates the causal relationship between the lack of CIITA and MHC-II loss.Conclusions. These data demonstrate that downregulation of MHC-II expression occurs by multiple distinct mechanisms in DLBCL. However, decreases in CIITA expression appear to be the most prevalent mechanism. (C) 2009 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.