title: Recurrent SETBP1 mutations in atypical chronic myeloid leukemia.
abstract: Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16-35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases.
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, Monza, Italy.
authors.forename: Rocco
authors.initials: R
authors.lastname: Piazza
authors.forename: Simona
authors.initials: S
authors.lastname: Valletta
authors.forename: Nils
authors.initials: N
authors.lastname: Winkelmann
authors.forename: Sara
authors.initials: S
authors.lastname: Redaelli
authors.forename: Roberta
authors.initials: R
authors.lastname: Spinelli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pirola
authors.forename: Laura
authors.initials: L
authors.lastname: Antolini
authors.forename: Luca
authors.initials: L
authors.lastname: Mologni
authors.forename: Carla
authors.initials: C
authors.lastname: Donadoni
authors.forename: Elli
authors.initials: E
authors.lastname: Papaemmanuil
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Boultwood
authors.forename: Fabio
authors.initials: F
authors.lastname: Rossi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gaipa
authors.forename: Greta P
authors.initials: GP
authors.lastname: De Martini
authors.forename: Paola Francia
authors.initials: PF
authors.lastname: di Celle
authors.forename: Hyun Gyung
authors.initials: HG
authors.lastname: Jang
authors.forename: Valeria
authors.initials: V
authors.lastname: Fantin
authors.forename: Graham R
authors.initials: GR
authors.lastname: Bignell
authors.forename: Vera
authors.initials: V
authors.lastname: Magistroni
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.forename: Enrico Maria
authors.initials: EM
authors.lastname: Pogliani
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Chase
authors.forename: William J
authors.initials: WJ
authors.lastname: Tapper
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
authors.forename: Carlo
authors.initials: C
authors.lastname: Gambacorti-Passerini
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins; D059472:Exome; D056488:Histone Chaperones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D054438:Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative / Q000235:genetics* / Q000401:mortality; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D054648:Protein Phosphatase 2 / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D009687:Nuclear Proteins; C513473:SET protein, human; C425066:SETBP1 protein, human; D014157:Transcription Factors; D054648:Protein Phosphatase 2