Document Detail

Up-regulation of survivin by the E2A-HLF chimera is indispensable for the survival of t(17;19)-positive leukemia cells.
MedLine Citation:
PMID:  19887369     Owner:  NLM     Status:  MEDLINE    
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.
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 Look; Toshiya Inaba
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-11-02
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2010-01-11     Completed Date:  2010-02-08     Revised Date:  2013-05-31    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1850-60     Citation Subset:  IM    
Department of Pediatrics, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan.
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MeSH Terms
Base Sequence
Basic Helix-Loop-Helix Transcription Factors / genetics,  metabolism*
Basic-Leucine Zipper Transcription Factors / genetics,  metabolism*
Caspases / metabolism
Cell Cycle / genetics
Cell Line, Tumor
Cell Survival / genetics
Chromosomes, Human, Pair 17 / genetics
Chromosomes, Human, Pair 19 / genetics
Inhibitor of Apoptosis Proteins
Microtubule-Associated Proteins / genetics*
Molecular Sequence Data
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics,  pathology*
Precursor Cells, B-Lymphoid / cytology,  metabolism
Promoter Regions, Genetic / genetics
Recombinant Fusion Proteins / metabolism*
Transcriptional Activation
Translocation, Genetic / genetics*
Reg. No./Substance:
0/BIRC5 protein, human; 0/Basic Helix-Loop-Helix Transcription Factors; 0/Basic-Leucine Zipper Transcription Factors; 0/HLF protein, human; 0/Inhibitor of Apoptosis Proteins; 0/Microtubule-Associated Proteins; 0/Recombinant Fusion Proteins; 0/TCF3 protein, human; EC 3.4.22.-/Caspases

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