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Chronic lymphocytic leukemia

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

Leukemia volume 34, pages 115–127 (2020)Cite this article

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Abstract

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.

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Acknowledgements

Fabienne McClanahan (Barts Cancer Institute, Queen Mary University of London, UK) provided precious advice regarding the use of the in vivo disease model. The authors are immensely thankful also to Linda Jannetti, Sandra Richter, and Daniela Steinbrecher for their invaluable help in conducting the animal experiments, as well as to Karin Müller, Ellen Scheidhauer, and Nina Urban (all at the Department of Internal Medicine III, University Clinic Ulm) for the excellent technical assistance. In addition, we would like to thank the patients for generous donation of their blood samples. This work was supported by grants from the Deutsche José Carreras Leukämie-Stiftung (DJCLS 14R/2016), the Virtual Helmholtz Institute “Resistance against Apoptotis and Therapy” (VH-VI-404), DFG D-A-CH (ME 3667/3-1), the DFG SFB1074 projects B1/B2, and the Else Kröner Fresenius Stiftung (2012_A146). VC would like to thank for the support of the International Graduate School in Molecular Medicine Ulm at Ulm University, Germany.

Funding

D.M. secured financial support for the study through grants from the Deutsche José Carreras Leukämie-Stiftung (DJCLS 14R/2016), the Virtual Helmholtz Institute “Resistance against Apoptotis and Therapy” (VH-VI-404), DFG D-A-CH (ME 3667/3-1), the DFG SFB1074 projects B1/B2, and the Else Kröner Fresenius Stiftung (2012_A146).

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Author notes

  1. Nupur Bhattacharya

    Present address: Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA

  2. These authors contributed equally: Deyan Yordanov Yosifov, Irina Idler, Nupur Bhattacharya

Authors and Affiliations

  1. Department of Internal Medicine III, Ulm University, Ulm, Germany

    Deyan Yordanov Yosifov, Irina Idler, Nupur Bhattacharya, Michaela Reichenzeller, Viola Close, Annika Scheffold, Billy Michael Chelliah Jebaraj, Sabrina Kugler, Johannes Bloehdorn, Anja Weigel, Hartmut Döhner, Stephan Stilgenbauer & Daniel Mertens

  2. Cooperation Unit “Mechanisms of Leukemogenesis”, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Deyan Yordanov Yosifov, Irina Idler, Michaela Reichenzeller, Viola Close, Sabrina Kugler & Daniel Mertens

  3. Division of Redox Regulation, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Daria Ezerina & Tobias P. Dick

  4. Department I of Internal Medicine, Center of Integrated Oncology Cologne Bonn, University of Cologne, Cologne, Germany

    Jasmin Bahlo, Sandra Robrecht, Barbara Eichhorst & Kirsten Fischer

  5. Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research (IMMZ), Albert-Ludwigs-University (ALU), Freiburg, Germany

    Hauke Busch

  6. German Cancer Consortium (DKTK), Freiburg, Germany

    Hauke Busch

  7. Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany (DKFZ), Heidelberg, Germany

    Peter Lichter

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  1. Deyan Yordanov Yosifov
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Correspondence to Daniel Mertens.

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Yosifov, D.Y., Idler, I., Bhattacharya, N. et al. Oxidative stress as candidate therapeutic target to overcome microenvironmental protection of CLL. Leukemia 34, 115–127 (2020). https://doi.org/10.1038/s41375-019-0513-x

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