Universität zu Köln

Knittel, Gero, Liedgens, Paul and Reinhardt, Hans C. (2015). Targeting ATM-deficient CLL through interference with DNA repair pathways. Front. Genet., 6. LAUSANNE: FRONTIERS MEDIA SA. ISSN 1664-8021

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Abstract

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world and accounts for approximately 30% of adult leukemias and 25% of non-Hodgkin lymphomas. The median age at diagnosis is 72 years. During recent years numerous genetic aberrations have been identified that are associated with an aggressive course of the disease and resistance against genotoxic chemotherapies. The DNA damage-responsive proapoptotic ATM-CHK2-p53 signaling pathway is frequently mutationally inactivated in CLL either through large deletions on chromosome 11 q (ATM) or 17p (TP53), or through protein-damaging mutations. Here, we focus on the role of ATM signaling for the immediate DNA damage response, DNA repair and leukemogenesis. We further discuss novel therapeutic concepts for the targeted treatment of ATM-defective CLLs. We specifically highlight the potential use of PARP1 and DNA-PKcs inhibitors for the treatment of ATM-mutant CLL clones. Lastly, we briefly discuss the current state of genetically engineered mouse models of the disease and emphasize the use of these preclinical tools as a common platform for the development and validation of novel therapeutic agents.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Knittel, Gero UNSPECIFIED UNSPECIFIED UNSPECIFIED Liedgens, Paul UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinhardt, Hans C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-401186
DOI:	10.3389/fgene.2015.00207
Journal or Publication Title:	Front. Genet.
Volume:	6
Date:	2015
Publisher:	FRONTIERS MEDIA SA
Place of Publication:	LAUSANNE
ISSN:	1664-8021
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CHRONIC LYMPHOCYTIC-LEUKEMIA; DOUBLE-STRAND BREAKS; CELL-CYCLE CHECKPOINTS; HOMOLOGOUS RECOMBINATION; ATAXIA-TELANGIECTASIA; DAMAGE RESPONSE; REQUIRES ATM; GENOMIC ABERRATIONS; CANCER; MUTATIONS Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/40118