Expression profiling of ATP-binding cassette transporters in childhood T-cell acute lymphoblastic leukemia.
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.
Efferth
Thomas
T
German Cancer Research Center M070, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. t.efferth@dkfz.de
Gillet
Jean-Pierre
JP
Sauerbrey
Axel
A
Zintl
Felix
F
Bertholet
Vincent
V
de Longueville
Françoise
F
Remacle
Jose
J
Steinbach
Daniel
D
D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000235:genetics*; D000293:Adolescent; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008962:Models, Theoretical; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D034622:RNA Interference; D014407:Tumor Cells, Cultured
D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C418186:ABCA2 protein, human; C441524:ABCA3 protein, human