Germ line ETV6 mutations in familial thrombocytopenia and hematologic malignancy

被引：279

作者：

Zhang, Michael Y. ^{[1
]}

Churpek, Jane E. ^{[2
,3
]}

Keel, Sioban B. ^{[4
]}

Walsh, Tom ^{[5
,6
]}

Lee, Ming K. ^{[5
,6
]}

Loeb, Keith R. ^{[1
,7
]}

Gulsuner, Suleyman ^{[5
,6
]}

Pritchard, Colin C. ^{[8
]}

Sanchez-Bonilla, Marilyn ^{[1
]}

Delrow, Jeffrey J. ^{[9
]}

Basom, Ryan S. ^{[9
]}

Forouhar, Melissa ^{[10
]}

Gyurkocza, Boglarka ^{[1
]}

Schwartz, Bradford S. ^{[11
,12
,13
]}

Neistadt, Barbara ^{[2
,3
]}

Marquez, Rafael ^{[2
,3
]}

Mariani, Christopher J. ^{[2
,3
]}

Coats, Scott A. ^{[1
]}

Hofmann, Inga ^{[14
,15
,16
]}

Lindsley, R. Coleman ^{[17
,18
]}

Williams, David A. ^{[14
,15
,16
]}

Abkowitz, Janis L. ^{[4
]}

Horwitz, Marshall S. ^{[7
]}

King, Mary-Claire ^{[5
,6
]}

Godley, Lucy A. ^{[2
]}

Shimamura, Akiko ^{[1
,19
,20
]}

机构：

[1] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA

[2] Univ Chicago, Ctr Clin Canc Genet, Sect Hematol Oncol, Chicago, IL 60637 USA

[3] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA

[4] Univ Washington, Div Hematol, Dept Med, Seattle, WA 98195 USA

[5] Univ Washington, Div Med Genet, Dept Med, Seattle, WA 98195 USA

[6] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[7] Univ Washington, Dept Pathol, Seattle, WA 98195 USA

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

[9] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA

[10] Madigan Army Med Ctr, Tacoma, WA 98431 USA

[11] Univ Wisconsin, Morgridge Inst Res, Madison, WI 53706 USA

[12] Univ Wisconsin, Dept Med, Madison, WI USA

[13] Univ Wisconsin, Dept Biomol Chem, Madison, WI USA

[14] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA

[15] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[16] Harvard Stem Cell Inst, Boston, MA USA

[17] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA

[18] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[19] Seattle Childrens Hosp, Seattle, WA USA

[20] Univ Washington, Dept Pediat, Seattle, WA 98195 USA

来源：

NATURE GENETICS | 2015年 / 47卷 / 02期

基金：

美国国家卫生研究院;

关键词：

ACUTE MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; MYELODYSPLASTIC SYNDROMES; INHERITED THROMBOCYTOPENIA; GENOMIC LANDSCAPE; GATA2; MUTATIONS; DNA-BINDING; TEL; GENE; PROTEIN;

D O I：

10.1038/ng.3177

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We report germline missense mutations in ETV6 segregating with the dominant transmission of thrombocytopenia and hematologic malignancy in three unrelated kindreds, defining a new hereditary syndrome featuring thrombocytopenia with susceptibility to diverse hematologic neoplasms. Two variants, p.Arg369Gln and p.Arg399Cys, reside in the highly conserved ETS DNA-binding domain. The third variant, p.Pro214Leu, lies within the internal linker domain, which regulates DNA binding. These three amino acid sites correspond to hotspots for recurrent somatic mutation in malignancies. Functional studies show that the mutations abrogate DNA binding, alter subcellular localization, decrease transcriptional repression in a dominant-negative fashion and impair hematopoiesis. These familial genetic studies identify a central role for ETV6 in hematopoiesis and malignant transformation. The identification of germline predisposition to cytopenias and cancer informs the diagnosis and medical management of at-risk individuals.

引用

页码：180 / 185

页数：6

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