AML1/ETO-induced survivin expression inhibits transcriptional regulation of myeloid differentiation

被引:15
作者
Balkhi, Mumtaz Yaseen [1 ]
Christopeit, Maximilian [1 ]
Chen, Yong [1 ]
Geletu, Mulu [1 ]
Behre, Gerhard [1 ]
机构
[1] Univ Halle Wittenberg, Clin Internal Med 4, State Ctr Cell & Gene Therapy, Bone Marrow Transplantat Unit, Halle, Germany
关键词
D O I
10.1016/j.exphem.2008.05.008
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective. The (8;21)(q22;q22) chromosomal translocation, which involves AML1 gene on chromosome 21 and the ETO gene on chromosome 8, generates an AML1/ETO fusion. AML1/ETO is associated with 15% of acute myeloid leukemia (AML) cases. The fusion gene is a dominant inhibitor of myeloid-specific genes, notably AML1, CCAAT/enhancer-binding protein-alpha (C/EBP alpha), and myeloperoxidase (MPO). In this study, we investigated the role of antiapoptosis gene survivin as a target of AML1/ETO-related leukemia. Materials and Methods. Through the combination of reporter assays, electrophoretic mobility shift assay, quantitative real-time polymerase chain reaction analysis, and short hairpin RNA (shRNA)- mediated knockdown of genes, we showed that survivin is a critical target of AML1/ETO. Biological studies were performed in cell lines and primary human CD 34(+) cells. Results. In this study, we have shown that ectopic expression of AML1/ETO induces survivin gene expression in both a cell line model and in the primary human hematopoietic CD34(+) cells. Reporter assays demonstrate that ectopically expressed AML1/ETO activates survivin promoter. Endogenous AML1/ETO derived from the Kasumi-1 cell line nuclear extract binds physically to the AML1 core enhancer-binding sequence, TGTGGT, derived from the survivin promotor. Knockdown of survivin expression by shRNA in ectopically expressed AML1/ETO myeloid leukemia cell lines restores expression of C/EBP alpha, granulocyte colony-stimulating factor receptor, and MPO genes, which leads to their growth arrest and granulocytic differentiation. Conclusions. Our results demonstrate that survivin gene acts as a critical mediator of AML1/ETO-induced late oncogeneic events. (c) 2008 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.
引用
收藏
页码:1449 / 1460
页数:12
相关论文
共 35 条
  • [1] Targeted therapy by disabling crossroad signaling networks:: the survivin paradigm
    Altieri, DC
    [J]. MOLECULAR CANCER THERAPEUTICS, 2006, 5 (03) : 478 - 482
  • [2] Validating survivin as a cancer therapeutic target
    Altieri, DC
    [J]. NATURE REVIEWS CANCER, 2003, 3 (01) : 46 - 54
  • [3] Proteomics of acute myeloid leukaemia: cytogenetic risk groups differ specifically in their proteome, interactome and post-translational protein modifications
    Balkhi, M. Y.
    Trivedi, A. K.
    Geletu, M.
    Christopeit, M.
    Bohlander, S. K.
    Behre, H. M.
    Behre, G.
    [J]. ONCOGENE, 2006, 25 (53) : 7041 - 7058
  • [4] Use of a promoterless Renilla luciferase vector as an internal control plasmid for transient co-transfection assays of Ras-mediated transcription activation
    Behre, G
    Smith, LT
    Tenen, DG
    [J]. BIOTECHNIQUES, 1999, 26 (01) : 24 - +
  • [5] ASSOCIATIONS BETWEEN MORPHOLOGY, KARYOTYPE, AND CLINICAL-FEATURES IN MYELOID LEUKEMIAS
    BITTER, MA
    LEBEAU, MM
    ROWLEY, JD
    LARSON, RA
    GOLOMB, HM
    VARDIMAN, JW
    [J]. HUMAN PATHOLOGY, 1987, 18 (03) : 211 - 225
  • [6] ETO protein of t(8;21) AML is a corepressor for Bcl-6 B-cefl lymphorna oncoprotein
    Chevallier, N
    Corcoran, CM
    Lennon, C
    Hyjek, E
    Chadburn, A
    Bardwell, VJ
    Licht, JD
    Melnick, A
    [J]. BLOOD, 2004, 103 (04) : 1454 - 1463
  • [7] ERICKSON P, 1992, BLOOD, V80, P1825
  • [8] p300 Coactivates the adipogenic transcription factor CCAAT/enhancer-binding protein α
    Erickson, RL
    Hemati, N
    Ross, SE
    MacDougald, OA
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (19) : 16348 - 16355
  • [9] Ferrara FF, 2001, CANCER RES, V61, P2
  • [10] Regulation of the inhibitor-of-apoptosis family member survivin in normal cord blood and bone marrow CD34+ cells by hematopoietic growth factors:: implication of survivin expression in normal hematopoiesis
    Fukuda, S
    Pelus, LM
    [J]. BLOOD, 2001, 98 (07) : 2091 - 2100