title: Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome.
abstract: 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-beta-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-beta-synthase overexpression and altered folate homeostasis that becomes fixed as the ability to repair DNA damage is compromised.
authors.affiliation: Department of Nutrition and Food Science, Wayne State University, Detroit, MI, USA.
authors.forename: Diane C
authors.initials: DC
authors.lastname: Cabelof
authors.forename: Hiral V
authors.initials: HV
authors.lastname: Patel
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.forename: Holly
authors.initials: H
authors.lastname: van Remmen
authors.forename: Larry H
authors.initials: LH
authors.lastname: Matherly
authors.forename: Yubin
authors.initials: Y
authors.lastname: Ge
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Taub
mesh_terms: D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002648:Child; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D004314:Down Syndrome / Q000150:complications / Q000235:genetics*; D005260:Female; D005333:Fetus / Q000378:metabolism; D050982:GATA1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D020440:Gene Duplication; D020022:Genetic Predisposition to Disease; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000209:etiology / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000502:physiology; D016254:Mutagenesis, Insertional / Q000502:physiology
chemical_list: D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D003541:Cystathionine beta-Synthase