Universität zu Köln

Yosifov, Deyan Yordanov ORCID: 0000-0002-5473-4398, Idler, Irina, Bhattacharya, Nupur, Reichenzeller, Michaela, Close, Viola, Ezerina, Daria ORCID: 0000-0002-3104-7093, Scheffold, Annika, Jebaraj, Billy Michael Chelliah, Kugler, Sabrina, Bloehdorn, Johannes, Bahlo, Jasmin, Robrecht, Sandra, Eichhorst, Barbara, Fischer, Kirsten, Weigel, Anja, Busch, Hauke ORCID: 0000-0003-4763-4521, Lichter, Peter, Doehner, Hartmut, Dick, Tobias P., Stilgenbauer, Stephan and Mertens, Daniel ORCID: 0000-0003-0227-7188 (2020). Oxidative stress as candidate therapeutic target to overcome microenvironmental protection of CLL. Leukemia, 34 (1). S. 115 - 128. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5551

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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-1 alpha 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Yosifov, Deyan Yordanov UNSPECIFIED orcid.org/0000-0002-5473-4398 UNSPECIFIED Idler, Irina UNSPECIFIED UNSPECIFIED UNSPECIFIED Bhattacharya, Nupur UNSPECIFIED UNSPECIFIED UNSPECIFIED Reichenzeller, Michaela UNSPECIFIED UNSPECIFIED UNSPECIFIED Close, Viola UNSPECIFIED UNSPECIFIED UNSPECIFIED Ezerina, Daria UNSPECIFIED orcid.org/0000-0002-3104-7093 UNSPECIFIED Scheffold, Annika UNSPECIFIED UNSPECIFIED UNSPECIFIED Jebaraj, Billy Michael Chelliah UNSPECIFIED UNSPECIFIED UNSPECIFIED Kugler, Sabrina UNSPECIFIED UNSPECIFIED UNSPECIFIED Bloehdorn, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Bahlo, Jasmin UNSPECIFIED UNSPECIFIED UNSPECIFIED Robrecht, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Eichhorst, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Kirsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Weigel, Anja UNSPECIFIED UNSPECIFIED UNSPECIFIED Busch, Hauke UNSPECIFIED orcid.org/0000-0003-4763-4521 UNSPECIFIED Lichter, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Doehner, Hartmut UNSPECIFIED UNSPECIFIED UNSPECIFIED Dick, Tobias P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stilgenbauer, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Mertens, Daniel UNSPECIFIED orcid.org/0000-0003-0227-7188 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-351093
DOI:	10.1038/s41375-019-0513-x
Journal or Publication Title:	Leukemia
Volume:	34
Number:	1
Page Range:	S. 115 - 128
Date:	2020
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-5551
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CHRONIC LYMPHOCYTIC-LEUKEMIA; CARDIAC-GLYCOSIDES; STROMAL CELLS; CANCER; EXPRESSION; SENSITIVITY; RECEPTOR; EMETINE; GENES; PATHOGENESIS Multiple languages Oncology; Hematology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/35109