FOXO1 downregulation contributes to the oncogenic program of primary mediastinal B-cell lymphoma.
FOXO1 downregulation contributes to the oncogenic program of primary mediastinal B-cell lymphoma.
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FOXO1 下调有助于原发性纵隔 B 细胞淋巴瘤的致癌过程。
DOI：
10.18632/oncotarget.2107
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发表时间：
2014-07-30
期刊：
影响因子：
--
通讯作者：
Ushmorov A
中科院分区：
文献类型：
--
作者：
Xie L;Ritz O;Leithäuser F;Guan H;Färbinger J;Weitzer CD;Gehringer F;Bruederlein S;Holzmann K;Vogel MJ;Möller P;Wirth T;Ushmorov A
最近，我们发现在B细胞中高度表达的转录因子FOXO 1在经典霍奇金淋巴瘤（cHL）中下调。由于原发性纵隔B细胞淋巴瘤（PMBL）与cHL转录程序相似，我们研究了FOXO 1在该实体中的表达。通过免疫组化方法，我们发现FOXO 1在20例原发性PMBL中有19例缺失或低水平表达。PMBL细胞系再现了在原发病例中观察到的低FOXO 1表达。通过分析基因表达谱数据，我们发现在PMBL病例中FOXO 1表达与JAK 2呈负相关。通过小分子量抑制剂TG 101348靶向JAK 2活性导致MedB-1和U2940细胞系中FOXO 1 mRNA和蛋白表达上调，并且MYC抑制剂10058-F4增加MedB-1细胞中FOXO 1 mRNA。此外，在MedB-1细胞中，FOXO 1的表达被DNA甲基化抑制剂5-氮杂-2-脱氧胞苷和组蛋白去乙酰化酶抑制剂阿司他丁A强烈上调。由于FOXO 1启动子未甲基化，因此这种作用很可能是间接的。FOXO 1阴性MedB-1细胞系中的FOXO 1激活导致生长停滞和凋亡，这伴随着MYC和BCL 2L 1/BCL xL的抑制。因此，FOXO 1抑制可能有助于致癌程序和PMBL的表型。
Recently we have shown that the transcription factor FOXO1, highly expressed in B cells, is downregulated in classical Hodgkin lymphoma (cHL). As primary mediastinal B cell lymphoma (PMBL) has similarities with the cHL transcription program we investigated FOXO1 expression in this entity. By using immunohistochemistry we found that FOXO1 was absent or expressed at low levels in 19 of 20 primary PMBL cases. PMBL cell lines reproduce the low FOXO1 expression observed in primary cases. By analyzing gene expression profiling data we found that FOXO1 expression inversely correlated with JAK2 in PMBL cases. Targeting JAK2 activity by the small molecular weight inhibitor TG101348 resulted in upregulation of FOXO1 mRNA and protein expression in MedB-1 and U2940 cell lines, and the MYC inhibitor 10058-F4 increased FOXO1 mRNA in MedB-1 cells. Moreover, in MedB-1 cells FOXO1 expression was strongly upregulated by the inhibitor of DNA methylation 5-aza-2-deoxycytidine and by the histone deacetylase inhibitor trichostatin A. Since FOXO1 promoter was unmethylated, this effect is most likely indirect. FOXO1 activation in the FOXO1-negative MedB-1 cell line led to growth arrest and apoptosis, which was accompanied by repression of MYC and BCL2L1/BCLxL. Thus, FOXO1 repression might contribute to the oncogenic program and phenotype of PMBL.
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