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Title: NF-κB-p62-NRF2 survival signaling is associated with high ROR1 expression in chronic lymphocytic leukemia.

Authors: Sanchez-Lopez, Elsa; Ghia, Emanuela M; Antonucci, Laura; Sharma, Natasha; Rassenti, Laura Z; Xu, Jinyi; Sun, Beicheng; Kipps, Thomas J; Karin, Michael

Published In Cell Death Differ, (2020 07)

Abstract: 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 (ROR1Hi). ROR1Hi 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.

PubMed ID: 31992855 Exiting the NIEHS site

MeSH Terms: Antibodies, Monoclonal, Humanized/pharmacology; B-Cell Activating Factor/metabolism; Bridged Bicyclo Compounds, Heterocyclic/pharmacology; Cell Line, Tumor; Cell Survival/drug effects; Cytoprotection/drug effects; Gene Expression Regulation, Leukemic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell/genetics; Leukemia, Lymphocytic, Chronic, B-Cell/metabolism*; Leukemia, Lymphocytic, Chronic, B-Cell/pathology; Mechanistic Target of Rapamycin Complex 1/metabolism; NF-E2-Related Factor 2/metabolism*; NF-kappa B/metabolism*; Neoplasm Proteins/genetics; Neoplasm Proteins/metabolism; Prodrugs/pharmacology; RNA, Messenger/genetics; RNA, Messenger/metabolism; Reactive Oxygen Species/metabolism; Receptor Tyrosine Kinase-like Orphan Receptors/metabolism*; Sequestosome-1 Protein/metabolism*; Signal Transduction*/drug effects; Sulfonamides/pharmacology

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