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Characterization of Camptothecin-induced Genomic Changes in the Camptothecin-resistant T-ALL-derived Cell Line CPT-K5

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Characterization of Camptothecin-induced Genomic Changes in the Camptothecin-resistant T-ALL-derived Cell Line CPT-K5. / Kjeldsen, Eigil; Nielsen, Christine J F; Roy, Amit; Tesauro, Cinzia; Jakobsen, Ann-Katrine; Stougaard, Magnus; Knudsen, Birgitta R.

I: Cancer Genomics & Proteomics, Bind 15, Nr. 2, 03.03.2018, s. 91-114.

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@article{65fb288f50924144965608d4b24fa198,
title = "Characterization of Camptothecin-induced Genomic Changes in the Camptothecin-resistant T-ALL-derived Cell Line CPT-K5",
abstract = "Acquisition of resistance to topoisomerase I (TOP1)-targeting camptothecin (CPT) derivatives is a major clinical problem. Little is known about the underlying chromosomal and genomic mechanisms. We characterized the CPT-K5 cell line expressing mutant CPT-resistant TOP1 and its parental T-cell derived acute lymphoblastic leukemia CPT-sensitive RPMI-8402 cell line by karyotyping and molecular genetic methods, including subtractive oligo-based array comparative genomic hybridization (soaCGH) analysis. Karyotyping revealed that CPT-K5 cells had acquired additional structural aberrations and a reduced modal chromosomal number compared to RPMI-8402. soaCGH analysis identified vast copy number alterations and >200 unbalanced DNA breakpoints distributed unevenly across the chromosomal complement in CPT-K5. In addition, the short tandem repeat alleles were found to be highly different between CPT-K5 and its parental cell line. We identified copy number alterations affecting genes important for maintaining genome integrity and reducing CPT-induced DNA damage. We show for the first time that short tandem repeats are targets for TOP1 cleavage, that can be differentially stimulated by CPT.",
author = "Eigil Kjeldsen and Nielsen, {Christine J F} and Amit Roy and Cinzia Tesauro and Ann-Katrine Jakobsen and Magnus Stougaard and Knudsen, {Birgitta R}",
note = "Copyright{\textcopyright} 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.",
year = "2018",
month = mar,
day = "3",
doi = "10.21873/cgp.20068",
language = "English",
volume = "15",
pages = "91--114",
journal = "Cancer Genomics & Proteomics",
issn = "1109-6535",
publisher = "International Institute of Anticancer Research",
number = "2",

}

RIS

TY - JOUR

T1 - Characterization of Camptothecin-induced Genomic Changes in the Camptothecin-resistant T-ALL-derived Cell Line CPT-K5

AU - Kjeldsen, Eigil

AU - Nielsen, Christine J F

AU - Roy, Amit

AU - Tesauro, Cinzia

AU - Jakobsen, Ann-Katrine

AU - Stougaard, Magnus

AU - Knudsen, Birgitta R

N1 - Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

PY - 2018/3/3

Y1 - 2018/3/3

N2 - Acquisition of resistance to topoisomerase I (TOP1)-targeting camptothecin (CPT) derivatives is a major clinical problem. Little is known about the underlying chromosomal and genomic mechanisms. We characterized the CPT-K5 cell line expressing mutant CPT-resistant TOP1 and its parental T-cell derived acute lymphoblastic leukemia CPT-sensitive RPMI-8402 cell line by karyotyping and molecular genetic methods, including subtractive oligo-based array comparative genomic hybridization (soaCGH) analysis. Karyotyping revealed that CPT-K5 cells had acquired additional structural aberrations and a reduced modal chromosomal number compared to RPMI-8402. soaCGH analysis identified vast copy number alterations and >200 unbalanced DNA breakpoints distributed unevenly across the chromosomal complement in CPT-K5. In addition, the short tandem repeat alleles were found to be highly different between CPT-K5 and its parental cell line. We identified copy number alterations affecting genes important for maintaining genome integrity and reducing CPT-induced DNA damage. We show for the first time that short tandem repeats are targets for TOP1 cleavage, that can be differentially stimulated by CPT.

AB - Acquisition of resistance to topoisomerase I (TOP1)-targeting camptothecin (CPT) derivatives is a major clinical problem. Little is known about the underlying chromosomal and genomic mechanisms. We characterized the CPT-K5 cell line expressing mutant CPT-resistant TOP1 and its parental T-cell derived acute lymphoblastic leukemia CPT-sensitive RPMI-8402 cell line by karyotyping and molecular genetic methods, including subtractive oligo-based array comparative genomic hybridization (soaCGH) analysis. Karyotyping revealed that CPT-K5 cells had acquired additional structural aberrations and a reduced modal chromosomal number compared to RPMI-8402. soaCGH analysis identified vast copy number alterations and >200 unbalanced DNA breakpoints distributed unevenly across the chromosomal complement in CPT-K5. In addition, the short tandem repeat alleles were found to be highly different between CPT-K5 and its parental cell line. We identified copy number alterations affecting genes important for maintaining genome integrity and reducing CPT-induced DNA damage. We show for the first time that short tandem repeats are targets for TOP1 cleavage, that can be differentially stimulated by CPT.

U2 - 10.21873/cgp.20068

DO - 10.21873/cgp.20068

M3 - Journal article

C2 - 29496689

VL - 15

SP - 91

EP - 114

JO - Cancer Genomics & Proteomics

JF - Cancer Genomics & Proteomics

SN - 1109-6535

IS - 2

ER -