Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia

被引：454

作者：

Hahn, Christopher N. ^{[1
,2
]}

Chong, Chan-Eng ^{[1
,2
]}

Carmichael, Catherine L. ^{[3
]}

Wilkins, Ella J. ^{[3
]}

Brautigan, Peter J. ^{[1
]}

Li, Xiao-Chun ^{[1
]}

Babic, Milena ^{[1
]}

Lin, Ming ^{[1
]}

Carmagnac, Amandine ^{[3
]}

Lee, Young K. ^{[1
]}

Kok, Chung H. ^{[4
,5
]}

Gagliardi, Lucia ^{[1
]}

Friend, Kathryn L. ^{[6
]}

Ekert, Paul G. ^{[7
]}

Butcher, Carolyn M. ^{[4
,5
]}

Brown, Anna L. ^{[5
]}

Lewis, Ian D. ^{[2
,5
]}

To, L. Bik ^{[2
,5
]}

Timms, Andrew E. ^{[8
]}

Storek, Jan ^{[9
]}

Moore, Sarah ^{[1
]}

Altree, Meryl ^{[10
]}

Escher, Robert ^{[3
]}

Bardy, Peter G. ^{[5
]}

Suthers, Graeme K. ^{[10
,11
]}

D'Andrea, Richard J. ^{[2
,4
,5
]}

Horwitz, Marshall S. ^{[8
]}

Scott, Hamish S. ^{[1
,2
,3
,12
]}

机构：

[1] SA Pathol, Ctr Canc Biol, Dept Mol Pathol, Adelaide, SA, Australia

[2] Univ Adelaide, Sch Med, Adelaide, SA 5005, Australia

[3] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Mol Med Div, Parkville, Vic 3050, Australia

[4] Queen Elizabeth Hosp, Dept Haematol & Oncol, Woodville, SA 5011, Australia

[5] SA Pathol, Ctr Canc Biol, Dept Haematol, Adelaide, SA, Australia

[6] SA Pathol, Dept Paediat & Reprod Genet, Adelaide, SA, Australia

[7] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Cell Signalling & Cell Death Div, Parkville, Vic 3050, Australia

[8] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA

[9] Univ Calgary, Dept Med, Calgary, AB, Canada

[10] SA Pathol, SA Clin Genet Serv, Adelaide, SA, Australia

[11] Univ Adelaide, Dept Paediat, Adelaide, SA, Australia

[12] Univ Adelaide, Sch Mol & Biomed Sci, Adelaide, SA 5005, Australia

来源：

NATURE GENETICS | 2011年 / 43卷 / 10期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

TRANSCRIPTION FACTOR; GENE-EXPRESSION; RUNX1; APOPTOSIS; HEALTH;

D O I：

10.1038/ng.913

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We report the discovery of GATA2 as a new myelodysplastic syndrome (MDS)-acute myeloid leukemia (AML) predisposition gene. We found the same, previously unidentified heterozygous c. 1061C>T (p.Thr354Met) missense mutation in the GATA2 transcription factor gene segregating with the multigenerational transmission of MDS-AML in three families and a GATA2 c. 1063_1065delACA (p.Thr355del) mutation at an adjacent codon in a fourth MDS family. The resulting alterations reside within the second zinc finger of GATA2, which mediates DNA-binding and protein-protein interactions. We show differential effects of the mutations on the transactivation of target genes, cellular differentiation, apoptosis and global gene expression. Identification of such predisposing genes to familial forms of MDS and AML is critical for more effective diagnosis and prognosis, counseling, selection of related bone marrow transplant donors and development of therapies.

引用

页码：1012 / U130

页数：8

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