TEL/AML1 overcomes drug resistance through transcriptional repression of multidrug resistance-1 gene expression.
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.
Asakura
Keiko
K
Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Uchida
Hideo
H
Miyachi
Hayato
H
Kobayashi
Hiroyuki
H
Miyakawa
Yoshitaka
Y
Nimer
Stephen D
SD
Takahashi
Hiroyuki
H
Ikeda
Yasuo
Y
Kizaki
Masahiro
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D050676:Core Binding Factor Alpha 2 Subunit; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D015972:Gene Expression Regulation, Neoplastic; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D020014:K562 Cells; D009841:Oligonucleotides / Q000737:chemistry; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*; D014162:Transfection; D000097764:ETS Translocation Variant 6 Protein
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D050676:Core Binding Factor Alpha 2 Subunit; D004317:Doxorubicin; D009841:Oligonucleotides; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D012097:Repressor Proteins; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein