Universität zu Köln

Lohmann, G., Vasyutina, E., Bloehdorn, J., Reinart, N., Schneider, J. I., Babu, V., Knittel, G., Crispatzu, G., Mayer, P., Prinz, C., Muenzner, J. K., Biersack, B., Efremov, D. G., Chessa, L., Herling, C. D., Stilgenbauer, S., Hallek, M., Schobert, R., Reinhardt, H. C., Schumacher, B. and Herling, M. (2017). Targeting transcription-coupled nucleotide excision repair overcomes resistance in chronic lymphocytic leukemia. Leukemia, 31 (5). S. 1177 - 1187. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5551

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Abstract

Treatment resistance becomes a challenge at some point in the course of most patients with chronic lymphocytic leukemia (CLL). This applies to fludarabine-based regimens, and is also an increasing concern in the era of more targeted therapies. As cells with low-replicative activity rely on repair that triggers checkpoint-independent noncanonical pathways, we reasoned that targeting the nucleotide excision repair (NER) reaction addresses a vulnerability of CLL and might even synergize with fludarabine, which blocks the NER gap-filling step. We interrogated here especially the replication-independent transcription-coupled-NER ((TC)-NER) in prospective trial patients, primary CLL cultures, cell lines and mice. We screen selected (TC)-NER-targeting compounds as experimental (illudins) or clinically approved (trabectedin) drugs. They inflict transcription-stalling DNA lesions requiring TC-NER either for their removal (illudins) or for generation of lethal strand breaks (trabectedin). Genetically defined systems of NER deficiency confirmed their specificity. They selectively and efficiently induced cell death in CLL, irrespective of high-risk cytogenetics, IGHV status or clinical treatment history, including resistance. The substances induced ATM/p53-independent apoptosis and showed marked synergisms with fludarabine. Trabectedin additionally perturbed stromal-cell protection and showed encouraging antileukemic profiles even in aggressive and transforming murine CLL. This proof-of-principle study established (TC)-NER as a mechanism to be further exploited to resensitize CLL cells.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Lohmann, G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vasyutina, E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bloehdorn, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinart, N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schneider, J. I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Babu, V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Knittel, G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Crispatzu, G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mayer, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Prinz, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Muenzner, J. K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Biersack, B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Efremov, D. G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Chessa, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Herling, C. D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stilgenbauer, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schobert, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinhardt, H. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schumacher, B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Herling, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-232826
DOI:	10.1038/leu.2016.294
Journal or Publication Title:	Leukemia
Volume:	31
Number:	5
Page Range:	S. 1177 - 1187
Date:	2017
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-5551
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language FLUDARABINE-MEDIATED INHIBITION; DNA-REPAIR; ANTITUMOR-ACTIVITY; TRANSGENIC MOUSE; TRABECTEDIN; IROFULVEN; CANCER; CELLS; EXPRESSION; APOPTOSIS Multiple languages Oncology; Hematology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23282