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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Base Sequence, CCAAT-Enhancer-Binding Protein-alpha, Cell Differentiation, Core Binding Factor Alpha 2 Subunit, Granulocytes, Humans, Inhibitor of Apoptosis Proteins, Microtubule-Associated Proteins, Molecular Sequence Data, Neoplasm Proteins, Oncogene Proteins, Fusion, Promoter Regions, Genetic, RNA, Small Interfering, RUNX1 Translocation Partner 1 Protein, Survivin, Transcription, Genetic.
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Does aML1/ETO-induced survivin expression inhibit transcriptional regulation of myeloid differentiation? Context: 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/EBPalpha), and myeloperoxidase (MPO). In this study, we investigated the role of antiapoptosis gene survivin as a target of AML1/ETO-related leukemia. 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. 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/EBPalpha, granulocyte colony-stimulating factor receptor, and MPO genes, which leads to their growth arrest and granulocytic differentiation.
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Our results demonstrate that survivin gene acts as a critical mediator of AML1/ETO-induced late oncogeneic events. Final Decision: yes