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Prepublished online as a Blood First Edition Paper on October 17, 2002; DOI 10.1182/blood-2002-07-2337. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-07-2337v1 101/4/1551    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ge, Y. Articles by Taub, J. W. Search for Related Content PubMed PubMed Citation Articles by Ge, Y. Articles by Taub, J. W. Related Collections Neoplasia Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 February 2003, Vol. 101, No. 4, pp. 1551-1557 NEOPLASIA Transcriptional regulation of the cystathionine--synthase gene in Down syndrome and non-Down syndrome megakaryocytic leukemia cell lines Yubin Ge, Tanya L. Jensen, Larry H. Matherly, and Jeffrey W. Taub From the Experimental and Clinical Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, and the Departments of Pharmacology and Pediatrics, Wayne State University School of Medicine, Detroit, MI. Children with Down syndrome (DS) with acute myeloid leukemia (AML) have significantly higher event-free survival rates compared to those with non-DS AML, linked to greater cytosine arabinoside (ara-C) sensitivity and higher transcript levels of the chromosome 21-localized gene, cystathionine--synthase (CBS), in DS myeloblasts. In this study, we examined the transcriptional regulation of the CBS gene in the DS megakaryocytic leukemia (AMkL) cell line, CMK, characterized by significantly higher CBS transcripts compared with the non-DS AMkL cell line, CMS. Rapid amplification of 5'-cDNA ends (5'-RACE) analysis demonstrated exclusive use of the CBS 1b promoter in the cell lines, and transient transfections with the full-length CBS 1b luciferase reporter gene construct showed 40-fold greater promoter activity in the CMK than CMS cells. Electrophoretic mobility shift assays showed enhanced binding of the transcription factors Sp1/Sp3 to 2 GC/GT-box elements (GC-f and GT-d) in the upstream regions of the CBS 1b promoter in CMK nuclear extracts and undetectable binding in CMS cells. Mutation of the GC-f- or GT-d-binding site resulted in an approximately 90% decrease of the CBS 1b promoter activity in transient transfections of CMK cells. Chromatin immunoprecipitation assays confirmed in vivo binding of Sp3, USF-1, and nuclear factor YA (NF-YA) to the CBS 1b promoter region in chromatin extracts of CMK and CMS cells. Decreased binding of Sp1/Sp3 in CMK nuclear extracts following treatment with calf alkaline phosphatase suggested a role for phosphorylation of Sp1/Sp3 in regulating CBS promoter activity and in the differential CBS expression between CMK and CMS cells. The results of this study with clinically relevant cell line models suggest potential mechanisms for disparate patterns of CBS gene expression in DS and non-DS myeloblasts and may, in part, explain the greater sensitivity to chemotherapy shown by patients with DS AML. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Edwards, C. Xie, K. M. LaFiura, A. A. Dombkowski, S. A. Buck, J. L. Boerner, J. W. Taub, L. H. Matherly, and Y. Ge RUNX1 regulates phosphoinositide 3-kinase/AKT pathway: role in chemotherapy sensitivity in acute megakaryocytic leukemia Blood, September 24, 2009; 114(13): 2744 - 2752. [Abstract] [Full Text] [PDF] D. Y. C. Wu, R. Wu, Y. Chen, N. Tarasova, and M. M. J. Chang PMA Stimulates MUC5B Gene Expression through an Sp1-Based Mechanism in Airway Epithelial Cells Am. J. Respir. Cell Mol. Biol., November 1, 2007; 37(5): 589 - 597. 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[Abstract] [Full Text] [PDF] S. Gurbuxani, P. Vyas, and J. D. Crispino Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome Blood, January 15, 2004; 103(2): 399 - 406. [Abstract] [Full Text] [PDF] D. G. Gilliland, C. T. Jordan, and C. A. Felix The Molecular Basis of Leukemia Hematology, January 1, 2004; 2004(1): 80 - 97. [Abstract] [Full Text] [PDF] Y. Ge, T. L. Jensen, L. H. Matherly, and J. W. Taub Physical and Functional Interactions between USF and Sp1 Proteins Regulate Human Deoxycytidine Kinase Promoter Activity J. Biol. Chem., December 12, 2003; 278(50): 49901 - 49910. [Abstract] [Full Text] [PDF]

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