| 论文作者 |
Liu, DD; Zhang, HH; Zhang, YW; Xiao, LP; Wang, JY; Liao, SY; Chen, HR; Wu, HL; Hu, YM; Jiang, YH; Wang, Q; Li, CF; Chen, PF; Zhan, Y; Li, LL; Xie, NX; Ye, DJ; Sun, DL; Hou, YY; Shi, YF; Liu, YZ; Zhu, J; Li, W; Shao, CK; Zhang, XR |
| 摘要 |
The stromal cells as the main component of the tumor micro-environment in germinal center B cell-like diffuse large B cell lymphoma (GCB-DLBCL) probably is accountable for therapy resistance and relapse. To investigate the interaction between tumor cells and stromal cells, we established GCB-DLBCL patient-derived xenograft models to isolate primary tumor cells and coculture them with stromal cells. Additionally, we presented GCB-DLBCL cases with histopathologic confirmation and analyzed the online databases to explore the underlying mechanisms. We demonstrated that CD40ligand (CD40L) expressed on stromal cells activated the CD40 pathway in GCB-DLBCL tumor cells, protecting tumor cells from apoptosis and up-regulating RANK ligand (RANKL). The RANKL expressed on tumor cells enhanced the expression of CD40L and BAFF in stromal cells, which in turn promoted tumor cells survival through activating NF-kappa B signaling. Significantly, the activation of CD40 pathway up-regulated KDM6B, a lysine-specific demethylase, and KDM6B further enhanced the transcription activity of NF-kappa B signaling, which has not been reported in B cells. Here, we provided compelling evidence that the interaction between stromal cells and tumor cells functions as a bona fide anti-apoptotic factor in GCB-DLBCL. This interaction mainly involves the CD40/RANK-KDM6B-NF-kappa B axis, which represents a promising therapeutic target for GCB-DLBCL. |
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