Somatic SETBP1 mutations in myeloid malignancies

Hideki Makishima, Kenichi Yoshida, Nhu Nguyen, Bartlomiej Przychodzen, Masashi Sanada, Yusuke Okuno, Kwok Peng Ng, Kristbjorn O. Gudmundsson, Bandana A. Vishwakarma, Andres Jerez, Ines Gomez Segui, Mariko Takahashi, Yuichi Shiraishi, Yasunobu Nagata, Kathryn Guinta, Hiraku Mori, Mikkael A. Sekeres, Kenichi Chiba, Hiroko Tanaka, Hideki MuramatsuHirotoshi Sakaguchi, Ronald L. Paquette, Michael A. McDevitt, Seiji Kojima, Yogen Saunthararajah, Satoru Miyano, Lee Yung Shih, Yang Du, Seishi Ogawa, Jaroslaw P. Maciejewski

Research output: Contribution to journalArticlepeer-review

170 Scopus citations


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). Closely positioned somatic SETBP1 mutations encoding changes in Asp868, Ser869, Gly870, Ile871 and Asp880, which match germline mutations in Schinzel-Giedion syndrome (SGS), 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. 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.

Original languageEnglish (US)
Pages (from-to)942-946
Number of pages5
JournalNature genetics
Issue number8
StatePublished - Aug 2013
Externally publishedYes

ASJC Scopus subject areas

  • Genetics


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