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

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

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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.

Original languageEnglish
Pages (from-to)1986-94
Number of pages9
JournalMolecular cancer therapeutics
Issue number8
Publication statusPublished - 2006


  • 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


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