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Mol Cancer Res. 2018 Mar;16(3):428-438. doi: 10.1158/1541-7786.MCR-17-0373. Epub 2017 Dec 8.

Imprecision and DNA Break Repair Biased towards Incompatible End Joining in Leukemia.

Author information

1
Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectious Disease, Rheumatology, Oncologic Center, Laboratory for Immunological and Molecular Cancer Research, Paracelsus Medical University Salzburg, Austria.
2
Cancer Cluster Salzburg, Salzburg, Austria.
3
School of Life Sciences, University of Warwick, Coventry, United Kingdom.
4
Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectious Disease, Rheumatology, Oncologic Center, Laboratory for Immunological and Molecular Cancer Research, Paracelsus Medical University Salzburg, Austria. r.geisberger@salk.at.
#
Contributed equally

Abstract

Cancer is a genetic disease caused by mutations and chromosomal abnormalities that contribute to uncontrolled cell growth. In addition, cancer cells can rapidly respond to conventional and targeted therapies by accumulating novel and often specific genetic lesions leading to acquired drug resistance and relapsing disease. In chronic lymphocytic leukemia (CLL), however, diverse chromosomal aberrations often occur. In many cases, improper repair of DNA double-strand breaks (DSB) is a major source for genomic abnormalities. Therefore, this study examined the repair of DNA DSBs by nonhomologous end joining (NHEJ) in CLL by performing plasmid-based repair assays in primary CLL cells and normal B cells, isolated from patients, as well as TALEN/Cas9-induced chromosomal deletions in the CLL cell line Mec1. It is demonstrated that DNA repair is aberrant in CLL cells, featuring perturbed DNA break structure preference with efficient joining of noncohesive ends and more deletions at repair junctions. In addition, increased microhomology-mediated end joining (MMEJ) of DNA substrates was observed in CLL together with increased expression of MMEJ-specific repair factors. In summary, these data identify major differences in DNA repair efficiency between CLL cells and normal B cells isolated from patients.Implications: This study suggests inherently aberrant DNA DSB repair in the acquisition of subclonal genomic structural variations important for clonal evolution and treatment resistance in CLL. Mol Cancer Res; 16(3); 428-38. ©2017 AACR.

PMID:
29222170
PMCID:
PMC5837005
DOI:
10.1158/1541-7786.MCR-17-0373
[Indexed for MEDLINE]
Free PMC Article

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