| Literature DB >> 19887369 |
Mayuko Okuya1, 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 Look, Toshiya Inaba.
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.Entities:
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Year: 2009 PMID： 19887369 PMCID： PMC2804343 DOI： 10.1074/jbc.M109.023762
Source DB: PubMed Journal: J Biol Chem ISSN： 0021-9258 Impact factor: 5.157