Genomic imbalances in drug-resistant T-cell acute lymphoblastic CEM leukemia cell lines

Autoren

Thomas Efferth
Irmgard Verdorfer
Hayato Miyachi
Axel Sauerbrey
Hans G Drexler
Christopher R Chitambar
Michelle Haber
Erich Gebhart

DOI

10.1006/bcmd.2002.0530

ISSN

1079-9796

Ausgabe der Veröffentlichung

1

Zeitschrift

Blood Cells, Molecules, and Diseases

Sprache

en

Paginierung

1 - 13

Datum der Veröffentlichung

2002

Status

Published

Herausgeber

Elsevier BV

Herausgeber URL

http://dx.doi.org/10.1006/bcmd.2002.0530

Datum der Datenerfassung

2020

Titel

Genomic Imbalances in Drug-Resistant T-Cell Acute Lymphoblastic CEM Leukemia Cell Lines

Ausgabe der Zeitschrift

29

Data source: Crossref

Abstract

Ten T-cell acute lymphoblastic (T-ALL) CEM cell lines selected for resistance toward methotrexate (CEM/MTX60PGA, CEM/MTX140LV, CEM/MTX1500LV, CEM/MTX5000PGA, CEM/MTXR1, CEM/MTXR2, and CEM/MTXR3), doxorubicin (CEM/ADR5000), vincristine (CEM/VCR1000), or hydroxyurea (CEM/HUR90), respectively, and parental drug-sensitive CCRF-CEM cells were analyzed using comparative genomic hybridization. Most genomic imbalances were not specific for drug resistance, as they were found in both parental and drug-resistant lines. Three aberrations were common to all or most cell lines analyzed: dim(5q35), dim(9p21p24), and enh(20q). We were concerned on those imbalances which were specifically present in drug-resistant but not in drug-sensitive cells. All methotrexate-resistant cell lines were characterized by an enhancement or an amplification of 5q13. The methotrexate resistance-conferring dihydrofolate reductase (DHFR) gene is located at this locus. Gain of DHFR was verified by PCR analyses. CEM/MTX60PGA, CEM/MTX140LV, CEM/MTX1500LV, and CEM/MTX5000PGA showed enh(14q21qter) and CEM/MTX5000PGA amp(5p13p15.2). These two loci harbor the methylenetetrahydrofolate dehydrogenase (MTHFD1) and 5'-methyltetrahdrofolate-homocysteine methyltransferase reductase (MTRR) genes, both of which are involved in folate metabolism. Their gain indicates a role in methotrexate resistance. A loss of 4q35 was found in CEM/MTXR2, CEM/MTXR3, and CEM/ADR5000 where the proapoptotic caspase-3 gene is located. The thioredoxin (TXN) locus 9q31 was enhanced in CEM/ADR5000 and CEM/MTX5000PGA cells. 2p22pter was increased in hydroxyurea-resistant CEM/HUR90 cells. Ribonucleotide reductase polypeptide M2 (RRM2), which confers resistance to hydroxyurea, resides at this locus. Other specific genomic imbalances in drug-resistant cell lines were dim(1p36.5), enh(4p), dim(8p22pter), enh(12p13), dim(17p), enh(18q12), enh(21q22.2), dim(21q22.2), and dim(22q13). All genomic imbalances were subjected to hierarchical cluster analysis and clustered image mapping to identify profiles of chromosomal aberrations in the cell lines. The obtained dendrograms allowed separation of imbalances common to all or most cell lines from other more individual aberrations. Furthermore, methotrexate-resistant cell lines clustered together. Our future efforts will be directed toward those imbalances which implicate still unknown candidate drug resistance genes.

Addresses

Virtual Campus Rhineland-Palatinate, P.O. Box 4380, 55033, Mainz, Germany. efferth@vcrp.de

Autoren

Thomas Efferth
Thomas Efferth
Irmgard Verdorfer
Hayato Miyachi
Axel Sauerbrey
Hans G Drexler
Christopher R Chitambar
Michelle Haber
Erich Gebhart

DOI

10.1006/bcmd.2002.0530

eISSN

1096-0961

Externe Identifier

PubMed Identifier: 12482398

Open access

false

ISSN

1079-9796

Ausgabe der Veröffentlichung

1

Zeitschrift

Blood cells, molecules & diseases

Schlüsselwörter

Tumor Cells, Cultured
Humans
Chromosome Aberrations
Hydroxyurea
Vincristine
Methotrexate
Doxorubicin
Antineoplastic Agents
Cluster Analysis
Karyotyping
Polymerase Chain Reaction
Nucleic Acid Hybridization
Drug Resistance, Neoplasm
Leukemia-Lymphoma, Adult T-Cell

Sprache

eng

Medium

Print

Paginierung

1 - 13

Datum der Veröffentlichung

2002

Status

Published

Datum der Datenerfassung

2002

Titel

Genomic imbalances in drug-resistant T-cell acute lymphoblastic CEM leukemia cell lines.

Sub types

Research Support, Non-U.S. Gov't
Journal Article

Ausgabe der Zeitschrift

29

Data source: Europe PubMed Central

Abstract

Ten T-cell acute lymphoblastic (T-ALL) CEM cell lines selected for resistance toward methotrexate (CEM/MTX60PGA, CEM/MTX140LV, CEM/MTX1500LV, CEM/MTX5000PGA, CEM/MTXR1, CEM/MTXR2, and CEM/MTXR3), doxorubicin (CEM/ADR5000), vincristine (CEM/VCR1000), or hydroxyurea (CEM/HUR90), respectively, and parental drug-sensitive CCRF-CEM cells were analyzed using comparative genomic hybridization. Most genomic imbalances were not specific for drug resistance, as they were found in both parental and drug-resistant lines. Three aberrations were common to all or most cell lines analyzed: dim(5q35), dim(9p21p24), and enh(20q). We were concerned on those imbalances which were specifically present in drug-resistant but not in drug-sensitive cells. All methotrexate-resistant cell lines were characterized by an enhancement or an amplification of 5q13. The methotrexate resistance-conferring dihydrofolate reductase (DHFR) gene is located at this locus. Gain of DHFR was verified by PCR analyses. CEM/MTX60PGA, CEM/MTX140LV, CEM/MTX1500LV, and CEM/MTX5000PGA showed enh(14q21qter) and CEM/MTX5000PGA amp(5p13p15.2). These two loci harbor the methylenetetrahydrofolate dehydrogenase (MTHFD1) and 5'-methyltetrahdrofolate-homocysteine methyltransferase reductase (MTRR) genes, both of which are involved in folate metabolism. Their gain indicates a role in methotrexate resistance. A loss of 4q35 was found in CEM/MTXR2, CEM/MTXR3, and CEM/ADR5000 where the proapoptotic caspase-3 gene is located. The thioredoxin (TXN) locus 9q31 was enhanced in CEM/ADR5000 and CEM/MTX5000PGA cells. 2p22pter was increased in hydroxyurea-resistant CEM/HUR90 cells. Ribonucleotide reductase polypeptide M2 (RRM2), which confers resistance to hydroxyurea, resides at this locus. Other specific genomic imbalances in drug-resistant cell lines were dim(1p36.5), enh(4p), dim(8p22pter), enh(12p13), dim(17p), enh(18q12), enh(21q22.2), dim(21q22.2), and dim(22q13). All genomic imbalances were subjected to hierarchical cluster analysis and clustered image mapping to identify profiles of chromosomal aberrations in the cell lines. The obtained dendrograms allowed separation of imbalances common to all or most cell lines from other more individual aberrations. Furthermore, methotrexate-resistant cell lines clustered together. Our future efforts will be directed toward those imbalances which implicate still unknown candidate drug resistance genes.

Autoren

Thomas Efferth
Irmgard Verdorfer
Hayato Miyachi
Axel Sauerbrey
Hans G Drexler
Christopher R Chitambar
Michelle Haber
Erich Gebhart

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/12482398

DOI

10.1006/bcmd.2002.0530

ISSN

1079-9796

Ausgabe der Veröffentlichung

1

Zeitschrift

Blood Cells Mol Dis

Schlüsselwörter

Antineoplastic Agents
Chromosome Aberrations
Cluster Analysis
Doxorubicin
Drug Resistance, Neoplasm
Humans
Hydroxyurea
Karyotyping
Leukemia-Lymphoma, Adult T-Cell
Methotrexate
Nucleic Acid Hybridization
Polymerase Chain Reaction
Tumor Cells, Cultured
Vincristine

Sprache

eng

Country

United States

Paginierung

1 - 13

PII

S1079979602905309

Datum der Veröffentlichung

2002

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2003

Titel

Genomic imbalances in drug-resistant T-cell acute lymphoblastic CEM leukemia cell lines.

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

29

Data source: PubMed

Genomic imbalances in drug-resistant T-cell acute lymphoblastic CEM leukemia cell lines

Tools