Recurrent SETBP1 mutations in atypical chronic myeloid leukemia

被引：314

作者：

Piazza, Rocco ^{[1
]}

Valletta, Simona ^{[1
]}

Winkelmann, Nils ^{[2
,3
]}

Redaelli, Sara ^{[1
]}

Spinelli, Roberta ^{[1
]}

Pirola, Alessandra ^{[1
]}

Antolini, Laura ^{[1
]}

Mologni, Luca ^{[1
]}

Donadoni, Carla ^{[1
]}

Papaemmanuil, Elli ^{[4
]}

Schnittger, Susanne ^{[5
]}

Kim, Dong-Wook ^{[6
]}

Boultwood, Jacqueline ^{[7
]}

Rossi, Fabio ^{[8
]}

Gaipa, Giuseppe ^{[9
]}

De Martini, Greta P. ^{[1
]}

Di Celle, Paola Francia ^{[10
]}

Jang, Hyun Gyung ^{[11
]}

Fantin, Valeria ^{[11
]}

Bignell, Graham R. ^{[4
]}

Magistroni, Vera ^{[1
]}

Haferlach, Torsten ^{[5
]}

Pogliani, Enrico Maria ^{[1
,12
]}

Campbell, Peter J. ^{[4
]}

Chase, Andrew J. ^{[2
,13
]}

Tapper, William J. ^{[2
,13
]}

Cross, Nicholas C. P. ^{[2
,13
]}

Gambacorti-Passerini, Carlo ^{[1
,14
]}

机构：

[1] Univ Milano Bicocca, Dept Hlth Sci, Monza, Italy

[2] Salisbury Dist Hosp, Wessex Reg Genet Lab, Salisbury, Wilts, England

[3] Univ Klinikum Jena, Klin Innere Med 2, Jena, Germany

[4] Wellcome Trust Sanger Inst, Canc Genome Project, Cambridge, England

[5] MLL, Munich, Germany

[6] Catholic Univ, Dept Hematol, Seoul, South Korea

[7] John Radcliffe Hosp, Leukaemia & Lymphoma Res Mol Hematol Unit, Oxford OX3 9DU, England

[8] San Gerardo Hosp, Immunotransfus Unit, Monza, Italy

[9] Univ Milano Bicocca, Pediat Clin, M Tettamanti Res Ctr, Monza, Italy

[10] Azienda Ospeda San Giovanni Battista Torino, Lab Oncol Mol, Ctr Ric Med Sperimentale CeRMS, Turin, Italy

[11] Agios Pharmaceut, Cambridge, MA USA

[12] San Gerardo Hosp, Hematol Unit, Monza, Italy

[13] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England

[14] San Gerardo Hosp, Hematol & Clin Res Unit, Monza, Italy

来源：

NATURE GENETICS | 2013年 / 45卷 / 01期

关键词：

DIFFERENTIAL EXPRESSION; SELF-RENEWAL; FUSION; EFFICIENT; ALIGNMENT; PROTEIN; KINASE; GALAXY; PP2A; GENE;

D O I：

10.1038/ng.2495

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：18 / U41

页数：10

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