Up-regulation of survivin by the E2A-HLF chimera is indispensable for the survival of t(17;19)-positive leukemia cells

Mayuko Okuya, Hidemitsu Kurosawa, Jiro Kikuchi, Yusuke Furukawa, Hirotaka Matsui, Daisuke Aki, Takayuki Matsunaga, Takeshi Inukai, Hiroaki Goto, Rachel A. Altura, Kenich Sugita, Osamu Arisaka, A. Thomas Lookand, Toshiya Inaba

Research output: Contribution to journalArticle

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Abstract

The E2A-HLF fusion transcription factor generated by t(17;19)(q22;p13) translocation is found in a small subset of pro-B cell acute lymphoblastic leukemias (ALLs) and promotes leukemogenesis by substituting for the antiapoptotic function of cytokines. Here we show that t(17;19) + ALL cells express Survivin at high levels and that a dominant negative mutant of E2A-HLF suppresses Survivin expression. Forced expression of E2A-HLF in t(17;19) - leukemia cells up-regulated Survivin expression, suggesting that Survivin is a downstream target of E2A-HLF. Analysis using a counterflow centrifugal elutriator revealed that t(17;19) + ALL cells express Survivin throughout the cell cycle. Reporter assays revealed that E2A-HLF induces survivin expression at the transcriptional level likely through indirect down-regulation of a cell cycle-dependent cis element in the promoter region. Down-regulation of Survivin function by a dominant negative mutant of Survivin or reduction of Survivin expression induced massive apoptosis throughout the cell cycle in t(17;19) + cells mainly through caspase-independent pathways involving translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus. AIF knockdown conferred resistance to apoptosis caused by down-regulation of Survivin function. These data indicated that reversal of AIF translocation by Survivin, which is induced by E2A-HLF throughout the cell cycle, is one of the key mechanisms in the protection of t(17;19) + leukemia cells from apoptosis.

Original languageEnglish
Pages (from-to)1850-1860
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number3
DOIs
Publication statusPublished - 2010 Jan 15
Externally publishedYes

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Apoptosis Inducing Factor
Leukemia
Up-Regulation
Cells
Cell Cycle
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Down-Regulation
Apoptosis
Mitochondria
B-Lymphoid Precursor Cells
Caspases
Genetic Promoter Regions
Assays
Transcription Factors
Fusion reactions
Cytokines

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Up-regulation of survivin by the E2A-HLF chimera is indispensable for the survival of t(17;19)-positive leukemia cells. / Okuya, Mayuko; Kurosawa, Hidemitsu; Kikuchi, Jiro; Furukawa, Yusuke; Matsui, Hirotaka; Aki, Daisuke; Matsunaga, Takayuki; Inukai, Takeshi; Goto, Hiroaki; Altura, Rachel A.; Sugita, Kenich; Arisaka, Osamu; Lookand, A. Thomas; Inaba, Toshiya.

In: Journal of Biological Chemistry, Vol. 285, No. 3, 15.01.2010, p. 1850-1860.

Research output: Contribution to journalArticle

Okuya, M, Kurosawa, H, Kikuchi, J, Furukawa, Y, Matsui, H, Aki, D, Matsunaga, T, Inukai, T, Goto, H, Altura, RA, Sugita, K, Arisaka, O, Lookand, AT & Inaba, T 2010, 'Up-regulation of survivin by the E2A-HLF chimera is indispensable for the survival of t(17;19)-positive leukemia cells', Journal of Biological Chemistry, vol. 285, no. 3, pp. 1850-1860. https://doi.org/10.1074/jbc.M109.023762
Okuya, Mayuko ; Kurosawa, Hidemitsu ; Kikuchi, Jiro ; Furukawa, Yusuke ; Matsui, Hirotaka ; Aki, Daisuke ; Matsunaga, Takayuki ; Inukai, Takeshi ; Goto, Hiroaki ; Altura, Rachel A. ; Sugita, Kenich ; Arisaka, Osamu ; Lookand, A. Thomas ; Inaba, Toshiya. / Up-regulation of survivin by the E2A-HLF chimera is indispensable for the survival of t(17;19)-positive leukemia cells. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 3. pp. 1850-1860.
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AU - Aki, Daisuke

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AU - Inukai, Takeshi

AU - Goto, Hiroaki

AU - Altura, Rachel A.

AU - Sugita, Kenich

AU - Arisaka, Osamu

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