TEL/AML1 overcomes drug resistance through transcriptional repression of multidrug resistance-1 gene expression

Keiko Asakura, Hideo Uchida, Hayato Miyachi, Hiroyuki Kobayashi, Yoshitaka Miyakawa, Stephen D. Nimer, Hiroyuki Takahashi, Yasuo Ikeda, Masahiro Kizaki

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

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 downregulate 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.

Original languageEnglish (US)
Pages (from-to)339-347
Number of pages9
JournalMolecular Cancer Research
Volume2
Issue number6
StatePublished - Jun 1 2004
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Asakura, K., Uchida, H., Miyachi, H., Kobayashi, H., Miyakawa, Y., Nimer, S. D., Takahashi, H., Ikeda, Y., & Kizaki, M. (2004). TEL/AML1 overcomes drug resistance through transcriptional repression of multidrug resistance-1 gene expression. Molecular Cancer Research, 2(6), 339-347.