FLT3-ITD induces ara-C resistance in myeloid leukemic cells through the repression of the ENT1 expression

Guilan Jin, Hiromichi Matsushita, Satomi Asai, Hideo Tsukamoto, Ryoichi Ono, Tetsuya Nosaka, Takashi Yahata, Shinichiro Takahashi, Hayato Miyachi

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

Abstract

Fms-related tyrosine kinase 3-internal tandem duplications (FLT3-ITD) are strongly associated with the refractory nature of acute myeloid leukemia (AML) by the standard combined chemotherapy. FLT3-ITD-expressing murine and human myeloid cell lines, HF6/FLT3-ITD and K562/FLT3-ITD cells, respectively, were developed in order to clarify whether FLT3-ITD is involved in the resistance to cytotoxic agents in AML. Both of these cell lines were specifically resistant to the pyrimidine analogue cytosine arabinoside (ara-C), an essential agent for AML, accompanied by the downregulation of equilibrative nucleoside transporter 1 (ENT1), a transporter responsible for the cellular uptake of ara-C. The ENT1 promoter activity and the cellular uptake of ara-C were reduced in K562/FLT3-ITD cells, and rescued by pretreating the cells with PKC412, a FLT3 inhibitor. In addition, the expression of hypoxia inducible factor 1 alpha subunit (HIF1A) transcripts was upregulated in K562/FLT3-ITD cells, and the induction of HIF-1α reduced the promoter activity of ENT1 gene in K562 cells. Taken together, these findings suggest that FLT3-ITD specifically induces ara-C resistance in leukemic cells by the repression of ENT1 expression, possibly through the upregulation of HIF-1α, while also partially accounting for the poor prognosis of AML with FLT3-ITD due to resistance to the standard chemotherapy protocols which include ara-C.

Original languageEnglish
Pages (from-to)1001-1006
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume390
Issue number3
DOIs
Publication statusPublished - 2009 Dec 18
Externally publishedYes

Keywords

  • Ara-C resistance
  • ENT1
  • FLT3-ITD
  • HIF-1α
  • Myeloid leukemia

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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