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Recurrent SETBP1 mutations in atypical chronic myeloid leukemia

Recurrent SETBP1 mutations in atypical chronic myeloid leukemia
Recurrent SETBP1 mutations in atypical chronic myeloid leukemia
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.
1061-4036
18-24
Piazza, Rocco
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Valletta, Simona
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Winkelmann, Nils
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Redaelli, Sara
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Spinelli, Roberta
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Pirola, Alessandra
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Antolini, Laura
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Mologni, Luca
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Donadoni, Carla
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Papaemmanuil, Elli
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Schnittger, Susanne
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Kim, Dong-Wook
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Boultwood, Jacqueline
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Rossi, Fabio
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Gaipa, Giuseppe
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De Martini, Greta P.
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di Celle, Paola Francia
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Jang, Hyun Gyung
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Fantin, Valeria
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Bignell, Graham R.
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Magistroni, Vera
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Haferlach, Torsten
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Pogliani, Enrico Maria
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Campbell, Peter J.
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Chase, Andrew J
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Tapper, William J.
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Cross, Nicholas C. P.
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Gambacorti-Passerini, Carlo
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Piazza, Rocco
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Valletta, Simona
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Winkelmann, Nils
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Redaelli, Sara
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Spinelli, Roberta
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Pirola, Alessandra
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Antolini, Laura
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Mologni, Luca
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Donadoni, Carla
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Papaemmanuil, Elli
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Schnittger, Susanne
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Kim, Dong-Wook
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Boultwood, Jacqueline
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Rossi, Fabio
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Gaipa, Giuseppe
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De Martini, Greta P.
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di Celle, Paola Francia
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Jang, Hyun Gyung
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Fantin, Valeria
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Bignell, Graham R.
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Magistroni, Vera
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Haferlach, Torsten
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Pogliani, Enrico Maria
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Campbell, Peter J.
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Chase, Andrew J
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Tapper, William J.
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Cross, Nicholas C. P.
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Gambacorti-Passerini, Carlo
743d071a-f7a3-46ee-927f-a475cb5ed2a3

Piazza, Rocco, Valletta, Simona, Winkelmann, Nils, Redaelli, Sara, Spinelli, Roberta, Pirola, Alessandra, Antolini, Laura, Mologni, Luca, Donadoni, Carla, Papaemmanuil, Elli, Schnittger, Susanne, Kim, Dong-Wook, Boultwood, Jacqueline, Rossi, Fabio, Gaipa, Giuseppe, De Martini, Greta P., di Celle, Paola Francia, Jang, Hyun Gyung, Fantin, Valeria, Bignell, Graham R., Magistroni, Vera, Haferlach, Torsten, Pogliani, Enrico Maria, Campbell, Peter J., Chase, Andrew J, Tapper, William J., Cross, Nicholas C. P. and Gambacorti-Passerini, Carlo (2013) Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nature Genetics, 45 (1), 18-24. (doi:10.1038/ng.2495). (PMID:23222956)

Record type: Article

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.

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More information

e-pub ahead of print date: 9 December 2012
Published date: January 2013
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 346185
URI: http://eprints.soton.ac.uk/id/eprint/346185
ISSN: 1061-4036
PURE UUID: 45131980-c131-45c3-ab76-adb6f6343589
ORCID for Andrew J Chase: ORCID iD orcid.org/0000-0001-6617-9953
ORCID for William J. Tapper: ORCID iD orcid.org/0000-0002-5896-1889
ORCID for Nicholas C. P. Cross: ORCID iD orcid.org/0000-0001-5481-2555

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Date deposited: 14 Dec 2012 10:15
Last modified: 23 Jul 2022 01:49

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Contributors

Author: Rocco Piazza
Author: Simona Valletta
Author: Nils Winkelmann
Author: Sara Redaelli
Author: Roberta Spinelli
Author: Alessandra Pirola
Author: Laura Antolini
Author: Luca Mologni
Author: Carla Donadoni
Author: Elli Papaemmanuil
Author: Susanne Schnittger
Author: Dong-Wook Kim
Author: Jacqueline Boultwood
Author: Fabio Rossi
Author: Giuseppe Gaipa
Author: Greta P. De Martini
Author: Paola Francia di Celle
Author: Hyun Gyung Jang
Author: Valeria Fantin
Author: Graham R. Bignell
Author: Vera Magistroni
Author: Torsten Haferlach
Author: Enrico Maria Pogliani
Author: Peter J. Campbell
Author: Andrew J Chase ORCID iD
Author: Carlo Gambacorti-Passerini

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