title: Somatic SETBP1 mutations in myeloid malignancies.
abstract: 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.
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Hideki
authors.initials: H
authors.lastname: Makishima
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Nhu
authors.initials: N
authors.lastname: Nguyen
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Przychodzen
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okuno
authors.forename: Kwok Peng
authors.initials: KP
authors.lastname: Ng
authors.forename: Kristbjorn O
authors.initials: KO
authors.lastname: Gudmundsson
authors.forename: Bandana A
authors.initials: BA
authors.lastname: Vishwakarma
authors.forename: Andres
authors.initials: A
authors.lastname: Jerez
authors.forename: Ines
authors.initials: I
authors.lastname: Gomez-Segui
authors.forename: Mariko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Nagata
authors.forename: Kathryn
authors.initials: K
authors.lastname: Guinta
authors.forename: Hiraku
authors.initials: H
authors.lastname: Mori
authors.forename: Mikkael A
authors.initials: MA
authors.lastname: Sekeres
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.forename: Hideki
authors.initials: H
authors.lastname: Muramatsu
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Sakaguchi
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Paquette
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDevitt
authors.forename: Seiji
authors.initials: S
authors.lastname: Kojima
authors.forename: Yogen
authors.initials: Y
authors.lastname: Saunthararajah
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.forename: Lee-Yung
authors.initials: LY
authors.lastname: Shih
authors.forename: Yang
authors.initials: Y
authors.lastname: Du
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016000:Cluster Analysis; D059472:Exome; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000401:mortality; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D023461:Myeloid Progenitor Cells / Q000378:metabolism / Q000473:pathology; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000401:mortality; D009687:Nuclear Proteins / Q000235:genetics*; D013601:T-Lymphocytes / Q000378:metabolism; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D009687:Nuclear Proteins; C425066:SETBP1 protein, human