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

被引:54
作者
Cabelof, Diane C. [2 ,3 ]
Patel, Hiral V. [2 ]
Chen, Qing [3 ]
van Remmen, Holly [4 ,5 ]
Matherly, Larry H. [3 ,6 ]
Ge, Yubin [3 ,6 ,7 ]
Taub, Jeffrey W. [1 ,3 ,7 ]
机构
[1] Childrens Hosp Michigan, Div Pediat Hematol Oncol, Detroit, MI 48201 USA
[2] Wayne State Univ, Dept Nutr & Food Sci, Detroit, MI 48202 USA
[3] Barbara Ann Karmanos Canc Inst, Dev Therapeut Program, Detroit, MI USA
[4] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX USA
[5] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX USA
[6] Wayne State Univ, Sch Med, Dept Pharmacol, Detroit, MI 48201 USA
[7] Wayne State Univ, Sch Med, Dept Pediat, Detroit, MI 48201 USA
关键词
ACUTE MEGAKARYOBLASTIC LEUKEMIA; TRANSIENT MYELOPROLIFERATIVE DISORDER; SINGLE-STRAND BREAKS; CYTOSINE DEAMINATION; LIPID-PEROXIDATION; HOMOCYSTEINE METABOLISM; ACQUIRED MUTATIONS; OXIDATIVE STRESS; FETAL LIVER; IN-VIVO;
D O I
10.1182/blood-2008-11-190330
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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. (Blood. 2009;114:2753-2763)
引用
收藏
页码:2753 / 2763
页数:11
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