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Blood, 24 September 2009, Vol. 114, No. 13, pp. 2753-2763. Prepublished online as a Blood First Edition Paper on July 24, 2009; DOI 10.1182/blood-2008-11-190330. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-11-190330v1 114/13/2753    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 CrossRef Google Scholar Articles by Cabelof, D. C. Articles by Taub, J. W. PubMed PubMed Citation Articles by Cabelof, D. C. Articles by Taub, J. W. Related Collections Myeloid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome Diane C. Cabelof1,2, Hiral V. Patel1, Qing Chen2, Holly van Remmen3, Larry H. Matherly2,4, Yubin Ge2,4,5, and Jeffrey W. Taub2,5,6 1 Department of Nutrition and Food Science, Wayne State University, Detroit, MI; 2 Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI; 3 Department of Cellular and Structural Biology and the Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio; Departments of 4 Pharmacology and 5 Pediatrics, Wayne State University School of Medicine, Detroit, MI; and 6 Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit Down syndrome (DS) children have a unique genetic susceptibility to develop leukemia, in particular, acute megakaryocytic leukemia (AMkL) associated with somatic GATA1 mutations. The study of this genetic susceptibility with the use of DS as a model of leukemogenesis has broad applicability to the understanding of leukemia in children overall. On the basis of the role of GATA1 mutations in DS AMkL, we analyzed the mutational spectrum of GATA1 mutations to begin elucidating possible mechanisms by which these sequence alterations arise. Mutational analysis revealed a predominance of small insertion/deletion, duplication, and base substitution mutations, including G:C>T:A, G:C>A:T, and A:T>G:C. This mutational spectrum points to potential oxidative stress and aberrant folate metabolism secondary to genes on chromosome 21 (eg, cystathionine-β-synthase, superoxide dismutase) as potential causes of GATA1 mutations. Furthermore, DNA repair capacity evaluated in DS and non-DS patient samples provided evidence that the base excision repair pathway is compromised in DS tissues, suggesting that inability to repair DNA damage also may play a critical role in the unique susceptibility of DS children to develop leukemia. A model of leukemogenesis in DS is proposed in which mutagenesis is driven by cystathionine-β-synthase overexpression and altered folate homeostasis that becomes fixed as the ability to repair DNA damage is compromised. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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