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

Deyan Yordanov Yosifov, Irina Idler, Nupur Bhattacharya, Michaela Reichenzeller, Viola Close, Daria Ezerina, Annika Scheffold, Billy Michael Chelliah Jebaraj, Sabrina Kugler, Johannes Bloehdorn, Jasmin Bahlo, Sandra Robrecht, Barbara Eichhorst, Kirsten Fischer, Anja Weigel, Hauke Busch, Peter Lichter, Hartmut Döhner, Tobias P. Dick, Stephan StilgenbauerDaniel Mertens*

*Corresponding author for this work
6 Citations (Scopus)


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.

Original languageEnglish
Issue number1
Pages (from-to)115-127
Number of pages13
Publication statusPublished - 01.01.2020


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