Xie Linka, Ritz Olga, Leithäuser Frank, Guan Hanfeng, Färbinger Johanna, Weitzer Clarissa D, Gehringer Franziska, Bruederlein Silke, Holzmann Karlheinz, Vogel Marion J, Möller Peter, Wirth Thomas, Ushmorov Alexey
Cancer Center of Union Hospital, Tongji Medical College, HuaZhong University of Science and Technology, Wuhan, China. Institute of Physiological Chemistry, University of Ulm, Germany.
Institute of Pathology, University of Ulm, Germany.
Oncotarget. 2014 Jul 30;5(14):5392-402. doi: 10.18632/oncotarget.2107.
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 Med-B1 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.
最近我们发现，在B细胞中高表达的转录因子FOXO1在经典型霍奇金淋巴瘤（cHL）中表达下调。由于原发性纵隔B细胞淋巴瘤（PMBL）与cHL转录程序有相似之处，我们研究了该实体中FOXO1的表达情况。通过免疫组织化学方法，我们发现20例原发性PMBL病例中有19例FOXO1缺失或低表达。PMBL细胞系重现了原发性病例中观察到的FOXO1低表达情况。通过分析基因表达谱数据，我们发现PMBL病例中FOXO1表达与JAK2呈负相关。用小分子抑制剂TG101348靶向JAK2活性可导致MedB-1和U2940细胞系中FOXO1 mRNA和蛋白表达上调，MYC抑制剂10058-F4可增加MedB-1细胞中FOXO1 mRNA的表达。此外，在MedB-1细胞中，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曲古抑菌素A可强烈上调FOXO1的表达。由于FOXO1启动子未甲基化，这种效应很可能是间接的。FOXO1阴性的Med-B1细胞系中FOXO1激活导致生长停滞和凋亡，同时伴随着MYC和BCL2L1/BCLxL的抑制。因此，FOXO1抑制可能有助于PMBL的致癌程序和表型。
