Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome

Diane C. Cabelof, Hiral V. Patel, Qing Chen, Holly Van Remmen, Larry H. Matherly, Yubin Ge, Jeffrey W. Taub

Research output: Contribution to journalArticle

52 Citations (Scopus)

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-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.

Original languageEnglish (US)
Pages (from-to)2753-2763
Number of pages11
JournalBlood
Volume114
Issue number13
DOIs
StatePublished - 2009

Fingerprint

Mutagenesis
Down Syndrome
Repair
Cystathionine
Folic Acid
Mutation
Leukemia, Megakaryoblastic, Acute
DNA
Leukemia
Genetic Predisposition to Disease
Oxidative stress
DNA Repair
DNA Damage
Chromosomes
Metabolism
Superoxide Dismutase
Substitution reactions
Genes
Chromosomes, Human, Pair 21
Tissue

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Cabelof, D. C., Patel, H. V., Chen, Q., Van Remmen, H., Matherly, L. H., Ge, Y., & Taub, J. W. (2009). Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome. Blood, 114(13), 2753-2763. https://doi.org/10.1182/blood-2008-11-190330

Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome. / Cabelof, Diane C.; Patel, Hiral V.; Chen, Qing; Van Remmen, Holly; Matherly, Larry H.; Ge, Yubin; Taub, Jeffrey W.

In: Blood, Vol. 114, No. 13, 2009, p. 2753-2763.

Research output: Contribution to journalArticle

Cabelof, DC, Patel, HV, Chen, Q, Van Remmen, H, Matherly, LH, Ge, Y & Taub, JW 2009, 'Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome', Blood, vol. 114, no. 13, pp. 2753-2763. https://doi.org/10.1182/blood-2008-11-190330
Cabelof, Diane C. ; Patel, Hiral V. ; Chen, Qing ; Van Remmen, Holly ; Matherly, Larry H. ; Ge, Yubin ; Taub, Jeffrey W. / Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome. In: Blood. 2009 ; Vol. 114, No. 13. pp. 2753-2763.
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