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Cancer Genes and Genomics

TEL/AML1 Overcomes Drug Resistance Through Transcriptional Repression of Multidrug Resistance-1 Gene Expression

¹ Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; ² Department of Internal Medicine, Tokyo Electric Power Company Hospital, Tokyo, Japan; Departments of ³ Laboratory Medicine and ⁴ Pharmacology, Tokai University School of Medicine, Kanagawa, Japan; ⁵ Division of Hematologic Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York; and ⁶ Department of Pediatrics, Yokohama City University School of Medicine, Kanagawa, Japan

Requests for reprints: Masahiro Kizaki, Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Phone: 81-3-5363-3785; Fax: 81-3-3353-3515. E-mail: makizaki{at}sc.itc.keio.ac.jp

The t(12;21)(p12;q22) chromosomal aberration, which is frequently observed in pediatric precursor B-cell acute lymphoblastic leukemia (ALL), generates the TEL/AML1 chimeric gene and protein. TEL/AML1-positive ALL has a favorable prognosis, and one possible reason is that this subtype of ALL rarely shows drug resistance. AML1/ETO, another AML1-containing chimeric protein, has been shown to transcriptionally repress the activity of the multidrug resistance-1 (MDR-1) gene promoter; thus, we examined whether TEL/AML1 also represses MDR-1 gene expression, possibly preventing the emergence of multidrug resistance. In this study, we show that the TEL/AML1 protein binds to the consensus AML1 binding site in the MDR-1 promoter and transcriptionally represses its activity. Following transient transfection of TEL/AML1 protein into Adriamycin-resistant K562/Adr cells, we also demonstrate that TEL/AML1 can down-regulate the expression of P-glycoprotein, a product of the MDR-1 gene, and restore the chemosensitivity to the cells. Furthermore, we report that MDR-1 mRNA levels in leukemic cells obtained from TEL/AML1-positive ALL patients are lower than those from TEL/AML1-negative ALL patients. Thus, TEL/AML1 protein acts as a transcriptional repressor of MDR-1 gene expression, and although TEL/AML1 has been implicated in leukemogenesis, its effects on the MDR-1 gene may contribute to the excellent prognosis of TEL/AML1-positive ALL with current therapy.