Format

Send to

Choose Destination
Leukemia. 2019 Jul 12. doi: 10.1038/s41375-019-0513-x. [Epub ahead of print]

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

Author information

1
Department of Internal Medicine III, Ulm University, Ulm, Germany.
2
Cooperation Unit "Mechanisms of Leukemogenesis", German Cancer Research Center (DKFZ), Heidelberg, Germany.
3
Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA.
4
Division of Redox Regulation, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany.
5
Department I of Internal Medicine, Center of Integrated Oncology Cologne Bonn, University of Cologne, Cologne, Germany.
6
Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research (IMMZ), Albert-Ludwigs-University (ALU), Freiburg, Germany.
7
German Cancer Consortium (DKTK), Freiburg, Germany.
8
Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany (DKFZ), Heidelberg, Germany.
9
Department of Internal Medicine III, Ulm University, Ulm, Germany. daniel.mertens@uniklinik-ulm.de.
10
Cooperation Unit "Mechanisms of Leukemogenesis", German Cancer Research Center (DKFZ), Heidelberg, Germany. daniel.mertens@uniklinik-ulm.de.

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.

PMID:
31300746
DOI:
10.1038/s41375-019-0513-x

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center