Expression profiling of ATP-binding cassette transporters in childhood T-cell acute lymphoblastic leukemia

Abstract

Abstract A major issue in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) is resistance to chemotherapeutic drugs. Multidrug resistance can be caused by ATP-binding cassette (ABC) transporters. The majority of these proteins have not yet been examined in T-ALL. Using a newly developed microarray for the simultaneous quantification of 38 ABC transporter genes, we observed a consistent overexpression of ABCA2/ABCA3 in clinical samples of ALL. Therefore, we analyzed the association of these two genes with drug resistance. Treatment of CCRF-CEM and Jurkat cells with methotrexate, vinblastine, or doxorubicin led to an induction of ABCA3 expression, whereas a significant increase of ABCA2 expression was only observed in Jurkat cells. To study the causal relationship of ABCA2/A3 overexpression with drug resistance, we applied RNA interference (RNAi) technology. RNAi specific for ABCA2 or ABCA3 led to a partial decrease of expression in these two ABC transporters. Upon cotreatment of RNAi for ABCA2 with methotrexate and vinblastine, a partial decrease of ABCA2 expression as well as a simultaneous increase of ABCA3 expression was observed. Vice versa, ABCA3 RNAi plus drugs decreased ABCA3 and increased ABCA2 expression. This indicates that down-regulation of one ABC transporter was compensated by the up-regulation of the other. Application of RNAi for both ABCA2 and ABCA3 resulted in a more efficient reduction of the expression of both transporters. As a consequence, a significant sensitization of cells to cytostatic drugs was achieved. In conclusion, ABCA2 and ABCA3 are expressed in many T-ALL and contribute to drug resistance. [Mol Cancer Ther 2006;5(8):1986–94]

Autoren

Thomas Efferth
Jean-Pierre Gillet
Axel Sauerbrey
Felix Zintl
Vincent Bertholet
Françoise de Longueville
Jose Remacle
Daniel Steinbach

DOI

10.1158/1535-7163.mct-06-0086

eISSN

1538-8514

ISSN

1535-7163

Ausgabe der Veröffentlichung

8

Zeitschrift

Molecular Cancer Therapeutics

Sprache

en

Online publication date

2006

Paginierung

1986 - 1994

Datum der Veröffentlichung

2006

Status

Published

Herausgeber

American Association for Cancer Research (AACR)

Herausgeber URL

http://dx.doi.org/10.1158/1535-7163.mct-06-0086

Datum der Datenerfassung

2022

Titel

Expression profiling of ATP-binding cassette transporters in childhood T-cell acute lymphoblastic leukemia

Ausgabe der Zeitschrift

5

Data source: Crossref

Abstract

A major issue in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) is resistance to chemotherapeutic drugs. Multidrug resistance can be caused by ATP-binding cassette (ABC) transporters. The majority of these proteins have not yet been examined in T-ALL. Using a newly developed microarray for the simultaneous quantification of 38 ABC transporter genes, we observed a consistent overexpression of ABCA2/ABCA3 in clinical samples of ALL. Therefore, we analyzed the association of these two genes with drug resistance. Treatment of CCRF-CEM and Jurkat cells with methotrexate, vinblastine, or doxorubicin led to an induction of ABCA3 expression, whereas a significant increase of ABCA2 expression was only observed in Jurkat cells. To study the causal relationship of ABCA2/A3 overexpression with drug resistance, we applied RNA interference (RNAi) technology. RNAi specific for ABCA2 or ABCA3 led to a partial decrease of expression in these two ABC transporters. Upon cotreatment of RNAi for ABCA2 with methotrexate and vinblastine, a partial decrease of ABCA2 expression as well as a simultaneous increase of ABCA3 expression was observed. Vice versa, ABCA3 RNAi plus drugs decreased ABCA3 and increased ABCA2 expression. This indicates that down-regulation of one ABC transporter was compensated by the up-regulation of the other. Application of RNAi for both ABCA2 and ABCA3 resulted in a more efficient reduction of the expression of both transporters. As a consequence, a significant sensitization of cells to cytostatic drugs was achieved. In conclusion, ABCA2 and ABCA3 are expressed in many T-ALL and contribute to drug resistance.

Addresses

German Cancer Research Center M070, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. t.efferth@dkfz.de

Autoren

Thomas Efferth
Thomas Efferth
Jean-Pierre Gillet
Axel Sauerbrey
Felix Zintl
Vincent Bertholet
Françoise de Longueville
Jose Remacle
Daniel Steinbach

DOI

10.1158/1535-7163.mct-06-0086

eISSN

1538-8514

Externe Identifier

PubMed Identifier: 16928819

Open access

false

ISSN

1535-7163

Ausgabe der Veröffentlichung

8

Zeitschrift

Molecular cancer therapeutics

Schlüsselwörter

Tumor Cells, Cultured
Humans
ATP-Binding Cassette Transporters
Multidrug Resistance-Associated Proteins
Antineoplastic Agents
Gene Expression Profiling
Down-Regulation
RNA Interference
Drug Resistance, Neoplasm
Models, Theoretical
Adolescent
Child
Child, Preschool
Female
Male
Leukemia-Lymphoma, Adult T-Cell

Sprache

eng

Medium

Print

Paginierung

1986 - 1994

Datum der Veröffentlichung

2006

Status

Published

Datum der Datenerfassung

2006

Titel

Expression profiling of ATP-binding cassette transporters in childhood T-cell acute lymphoblastic leukemia.

Sub types

Journal Article

Ausgabe der Zeitschrift

5

Data source: Europe PubMed Central

Abstract

A major issue in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) is resistance to chemotherapeutic drugs. Multidrug resistance can be caused by ATP-binding cassette (ABC) transporters. The majority of these proteins have not yet been examined in T-ALL. Using a newly developed microarray for the simultaneous quantification of 38 ABC transporter genes, we observed a consistent overexpression of ABCA2/ABCA3 in clinical samples of ALL. Therefore, we analyzed the association of these two genes with drug resistance. Treatment of CCRF-CEM and Jurkat cells with methotrexate, vinblastine, or doxorubicin led to an induction of ABCA3 expression, whereas a significant increase of ABCA2 expression was only observed in Jurkat cells. To study the causal relationship of ABCA2/A3 overexpression with drug resistance, we applied RNA interference (RNAi) technology. RNAi specific for ABCA2 or ABCA3 led to a partial decrease of expression in these two ABC transporters. Upon cotreatment of RNAi for ABCA2 with methotrexate and vinblastine, a partial decrease of ABCA2 expression as well as a simultaneous increase of ABCA3 expression was observed. Vice versa, ABCA3 RNAi plus drugs decreased ABCA3 and increased ABCA2 expression. This indicates that down-regulation of one ABC transporter was compensated by the up-regulation of the other. Application of RNAi for both ABCA2 and ABCA3 resulted in a more efficient reduction of the expression of both transporters. As a consequence, a significant sensitization of cells to cytostatic drugs was achieved. In conclusion, ABCA2 and ABCA3 are expressed in many T-ALL and contribute to drug resistance.

Autoren

Thomas Efferth
Jean-Pierre Gillet
Axel Sauerbrey
Felix Zintl
Vincent Bertholet
Françoise de Longueville
Jose Remacle
Daniel Steinbach

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/16928819

DOI

10.1158/1535-7163.MCT-06-0086

ISSN

1535-7163

Ausgabe der Veröffentlichung

8

Zeitschrift

Mol Cancer Ther

Schlüsselwörter

ATP-Binding Cassette Transporters
Adolescent
Antineoplastic Agents
Child
Child, Preschool
Down-Regulation
Drug Resistance, Neoplasm
Female
Gene Expression Profiling
Humans
Leukemia-Lymphoma, Adult T-Cell
Male
Models, Theoretical
Multidrug Resistance-Associated Proteins
RNA Interference
Tumor Cells, Cultured

Sprache

eng

Country

United States

Paginierung

1986 - 1994

PII

5/8/1986

Datum der Veröffentlichung

2006

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2006

Titel

Expression profiling of ATP-binding cassette transporters in childhood T-cell acute lymphoblastic leukemia.

Sub types

Journal Article

Ausgabe der Zeitschrift

5

Data source: PubMed

Expression profiling of ATP-binding cassette transporters in childhood T-cell acute lymphoblastic leukemia

Tools