Guan Hanfeng, Xie Linka, Wirth Thomas, Ushmorov Alexey
Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.
Oncotarget. 2016 Jun 14;7(24):36854-36864. doi: 10.18632/oncotarget.9210.
Although Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) derived from germinal or post germinal B cells, they have lost the B cell phenotype in the process of lymphomagenesis. The phenomenon can be at least partially explained by repression of B-cell-specific transcription factors including TCF3, early B-cell factor 1 (EBF1), SPI1/PU.1, and FOXO1, which are down-regulated by genetic and epigenetic mechanisms. The unique phenotype has been suspected to be advantageous for survival of HRS cells. Ectopic expression of some of these transcription factors (EBF1, PU.1, FOXO1) indeed impaired survival of cHL cells. Here we show that forced expression of TCF3 causes cell death and cell cycle arrest in cHL cell lines. Mechanistically, TCF3 overexpression modulated expression of multiple pro-apoptotic genes including BIK, APAF1, FASLG, BOK, and TNFRSF10A/DR4. We conclude that TCF3 inactivation contributes not only to extinguishing of B cell phenotype but also to cHL oncogenesis.
尽管经典型霍奇金淋巴瘤（cHL）的霍奇金和里德-斯特恩伯格（HRS）细胞源自生发中心或生发后B细胞，但它们在淋巴瘤发生过程中丧失了B细胞表型。这种现象至少可以部分通过包括TCF3、早期B细胞因子1（EBF1）、SPI1/PU.1和FOXO1在内的B细胞特异性转录因子的抑制来解释，这些转录因子通过遗传和表观遗传机制被下调。这种独特的表型被怀疑对HRS细胞的存活有利。其中一些转录因子（EBF1、PU.1、FOXO1）的异位表达确实损害了cHL细胞的存活。在这里，我们表明强制表达TCF3会导致cHL细胞系中的细胞死亡和细胞周期停滞。从机制上讲，TCF3过表达调节了多个促凋亡基因的表达，包括BIK、APAF1、FASLG、BOK和TNFRSF10A/DR4。我们得出结论，TCF3失活不仅有助于消除B细胞表型，而且有助于cHL的肿瘤发生。
