Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA.
Cell Death Differ. 2020 Jul;27(7):2206-2216. doi: 10.1038/s41418-020-0496-1. Epub 2020 Jan 28.
Progression of chronic lymphocytic leukemia (CLL) and resistance to therapy are affected by tumor microenvironmental factors. One such factor is B-cell activating factor (BAFF), a cytokine that is produced mainly by nurse-like cells (NLC) and enhances CLL cells survival and modulates response to therapy. In CLL cells, BAFF activates NF-κB signaling, but how NF-κB supports CLL survival is not entirely clear. In this study we show that BAFF induces accumulation of the signaling and autophagy adaptor p62/SQSTM1 in a manner dependent on NF-κB activation. p62 potentiates mTORC1 signaling and activates NRF2, the master regulator of the anti-oxidant response. We found that expression of NRF2 target genes, such as NAD(P)H quinone oxidoreductase 1 (NQO1), is particularly enriched in CLL cells with high ROR1 surface expression (ROR1). ROR1 CLL cells with elevated NQO1 expression exhibit resistance to drugs that induce ROS accumulation, such venetoclax. However, such cells are more sensitive to compound 29h, a pro-drug that only becomes active after being metabolized by NQO1. Accordingly, 29h sensitizes high NQO1 CLL cells to venetoclax. Collectively, our study unravels a previously unknown signaling network through which the NF-κB-p62-NRF2 axis protects ROR1-high CLL cells from ROS-inducing therapeutics.
慢性淋巴细胞白血病 (CLL) 的进展和对治疗的耐药性受到肿瘤微环境因素的影响。其中一个因素是 B 细胞激活因子 (BAFF)，一种主要由类护士细胞 (NLC) 产生的细胞因子，可增强 CLL 细胞的存活并调节对治疗的反应。在 CLL 细胞中，BAFF 激活 NF-κB 信号通路，但 NF-κB 如何支持 CLL 存活尚不完全清楚。在这项研究中，我们表明 BAFF 以依赖 NF-κB 激活的方式诱导信号和自噬接头 p62/SQSTM1 的积累。p62 增强 mTORC1 信号通路并激活 NRF2，这是抗氧化反应的主要调节因子。我们发现 NRF2 靶基因的表达，如 NAD(P)H 醌氧化还原酶 1 (NQO1)，在高 ROR1 表面表达 (ROR1) 的 CLL 细胞中特别丰富。表达 NQO1 的 ROR1 CLL 细胞对诱导 ROS 积累的药物（如 venetoclax）具有耐药性。然而，这些细胞对化合物 29h 更敏感，29h 是一种前药，只有在被 NQO1 代谢后才会变得活跃。因此，29h 使高 NQO1 CLL 细胞对 venetoclax 敏感。总的来说，我们的研究揭示了一个以前未知的信号网络，通过该网络，NF-κB-p62-NRF2 轴保护 ROR1 高的 CLL 细胞免受 ROS 诱导的治疗。
