Oxidative stress as candidate therapeutic target to overcome microenvironmental protection of CLL

• DOI: 10.1038/s41375-019-0513-x
• Publication Date: 2019-07-12T12:03:13Z
• Authors: Deyan Yordanov Yo...; Irina Idler; Nupur Bhattacharya; Michaela Reichenz...; Viola Close; Daria Ezerina; Annika Scheffold; Billy Michael Che...; Sabrina Kugler; Johannes Bloehdorn; Jasmin Bahlo; Sandra Robrecht; Barbara Eichhorst; Kirsten Fischer; Anja Weigel; Hauke Busch; Peter Lichter; Hartmut Döhner; Tobias P. Dick; Stephan Stilgenbauer; Daniel Mertens
• Keywords: 0303 health sciences; mice; Mesenchymal Stem Cells/metabolism; Leukemia, Lymphocytic, Chronic, B-Cell/pathology; Emetine; Oxidative Stress/drug effects; 610; Mesenchymal Stem Cells; Emetine/pharmacology; Leukemia, Lymphocytic, Chronic, B-Cell; Tumor Microenvironment/drug effects; Coculture Techniques; 3. Good health; Mice; Oxidative Stress; 03 medical and health sciences; 616; Tumor Microenvironment; Animals; Heterografts; Humans

Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental non-malignant cells for survival. We compared the transcriptomes of primary CLL cells cocultured or not with protective bone marrow stromal cells (BMSCs) and found that oxidative phosphorylation, mitochondrial function, and hypoxic signaling undergo most significant dysregulation in non-protected CLL cells, with the changes peaking at 6-8 h, directly before induction of apoptosis. A subset of CLL patients displayed a gene expression signature resembling that of cocultured CLL cells and had significantly worse progression-free and overall survival. To identify drugs blocking BMSC-mediated support, we compared the relevant transcriptomic changes to the Connectivity Map database. Correlation was found with the transcriptomic signatures of the cardiac glycoside ouabain and of the ipecac alkaloids emetine and cephaeline. These compounds were highly active against protected primary CLL cells (relative IC50's 287, 190, and 35 nM, respectively) and acted by repressing HIF-1α and disturbing intracellular redox homeostasis. We tested emetine in a murine model of CLL and observed decreased CLL cells in peripheral blood, spleen, and bone marrow, recovery of hematological parameters and doubling of median survival (31.5 vs. 15 days, P = 0.0001). Pathways regulating redox homeostasis are thus therapeutically targetable mediators of microenvironmental support in CLL cells.