Somatic SETBP1 mutations in myeloid malignancies

被引：213

作者：

Makishima, Hideki ^{[1
]}

Yoshida, Kenichi ^{[2
]}

Nhu Nguyen ^{[3
]}

Przychodzen, Bartlomiej ^{[1
]}

Sanada, Masashi ^{[2
,4
]}

Okuno, Yusuke ^{[2
,5
]}

Ng, Kwok Peng ^{[1
]}

Gudmundsson, Kristbjorn O. ^{[3
]}

Vishwakarma, Bandana A. ^{[3
]}

Jerez, Andres ^{[1
]}

Gomez-Segui, Ines ^{[1
]}

Takahashi, Mariko ^{[2
]}

Shiraishi, Yuichi ^{[6
]}

Nagata, Yasunobu ^{[2
]}

Guinta, Kathryn ^{[1
]}

Mori, Hiraku ^{[7
]}

Sekeres, Mikkael A. ^{[8
]}

Chiba, Kenichi ^{[6
]}

Tanaka, Hiroko ^{[9
]}

Muramatsu, Hideki ^{[5
]}

Sakaguchi, Hirotoshi ^{[5
]}

Paquette, Ronald L. ^{[10
]}

McDevitt, Michael A. ^{[11
]}

Kojima, Seiji ^{[5
]}

Saunthararajah, Yogen ^{[1
]}

Miyano, Satoru ^{[6
,9
]}

Shih, Lee-Yung ^{[12
]}

Du, Yang ^{[3
]}

Ogawa, Seishi ^{[2
,4
]}

Maciejewski, Jaroslaw P. ^{[1
]}

机构：

[1] Cleveland Clin, Taussig Canc Inst, Dept Translat Hematol & Oncol Res, Cleveland, OH 44106 USA

[2] Univ Tokyo, Grad Sch Med, Canc Genom Project, Tokyo, Japan

[3] Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA

[4] Kyoto Univ, Grad Sch Med, Dept Pathol & Tumor Biol, Kyoto, Japan

[5] Nagoya Univ, Grad Sch Med, Dept Pediat, Nagoya, Aichi 4648601, Japan

[6] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab DNA Informat Anal, Tokyo, Japan

[7] Showa Univ, Dept Hematol, Tokyo, Japan

[8] Cleveland Clin, Taussig Canc Inst, Dept Hematol Oncol & Blood Disorders, Cleveland, OH 44106 USA

[9] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab Sequence Anal, Tokyo, Japan

[10] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA

[11] Johns Hopkins Univ, Sch Med, Div Hematol & Hematol Malignancy, Dept Med & Oncol, Baltimore, MD USA

[12] Chang Gung Univ, Chang Gung Mem Hosp, Div Hematol Oncol, Dept Internal Med, Taipei, Taiwan

来源：

NATURE GENETICS | 2013年 / 45卷 / 08期

基金：

日本学术振兴会; 美国国家卫生研究院;

关键词：

UNIPARENTAL DISOMY; C-CBL; LEUKEMIA; ACTIVATION; TET2; RAS;

D O I：

10.1038/ng.2696

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Here we report whole-exome sequencing of individuals with various myeloid malignancies and identify recurrent somatic mutations in SETBP1, consistent with a recent report on atypical chronic myeloid leukemia (aCML)(1). Closely positioned somatic SETBP1 mutations encoding changes in Asp868, Ser869, Gly870, Ile871 and Asp880, which match germline mutations in Schinzel-Giedion syndrome (SGS)(2), were detected in 17% of secondary acute myeloid leukemias (sAML) and 15% of chronic myelomonocytic leukemia (CMML) cases. These results from deep sequencing demonstrate a higher mutational detection rate than reported with conventional sequencing methodology(3-5). Mutant cases were associated with advanced age and monosomy 7/deletion 7q (-7/del(7q)) constituting poor prognostic factors. Analysis of serially collected samples indicated that SETBP1 mutations were acquired during leukemic evolution. Transduction with mutant Setbp1 led to the immortalization of mouse myeloid progenitors that showed enhanced proliferative capacity compared to cells transduced with wild-type Setbp1. Somatic mutations of SETBP1 seem to cause gain of function, are associated with myeloid leukemic transformation and convey poor prognosis in myelodysplastic syndromes (MDS) and CMML.

引用

页码：942 / U298

页数：7

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