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Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms

Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms
Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms
The polycomb repressive complex 2 (PRC2) is a highly conserved histone H3 lysine 27 methyltransferase that regulates the expression of developmental genes. Inactivating mutations of the catalytic component of PRC2, EZH2, are seen in myeloid disorders. We reasoned that the other two core PRC2 components SUZ12 and EED may also be
mutational targets in these diseases, as well as associated factors such as Jarid2. SUZ12 mutations were identified in 1 of 2 cases with myelodysplastic/myeloproliferative neoplasm (MDS/MPN) with 17q aUPD and 2 of 2 myelofibrosis cases with focal 17q11 deletions. All three were missense mutations affecting the highly conserved VEFS domain. Analysis of a further 146 MDS/MPN cases revealed an additional VEFS domain mutant, yielding a total mutation frequency of 2/148 (1.4%). We did not find mutations of Jarid2 or EED in association with aUPD for chromosome 6p or 11q, respectively, however screening unselected cases identified missense mutations in EED (1/148; 1%) and Jarid2 (3/148; 2%). All three SUZ12 mutations tested and the EED mutation reduced PRC2 histone methyltransferase activity in vitro, thus demonstrating that PRC2 function may be compromised in myeloid disorders by mutation of distinct genes.
0006-4971
1208-1213
Score, Joannah
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Hidalgo-Curtis, Claire
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Jones, Amy V.
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Winkelmann, Nils
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Skinner, Alison
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Ward, Daniel
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Zoi, Katerina
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Ernst, Thomas
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Stegelmann, Frank
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Döhner, Konstanze
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Chase, A.
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Cross, Nicholas C.P.
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Score, Joannah
ea0db6ef-c17e-4915-b216-ac67c07b26b7
Hidalgo-Curtis, Claire
5aaa8cfa-7271-48ee-8538-27736ab3eaf2
Jones, Amy V.
3d296088-a099-45cf-b227-541ff59d800c
Winkelmann, Nils
b563bf37-a957-41ac-9caf-f3caf170d35b
Skinner, Alison
19f1d3b1-3f2b-4e42-b39c-ae0eb57ae3b2
Ward, Daniel
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Zoi, Katerina
0bcb986d-3fef-49dc-b9f8-18daf79e8bfb
Ernst, Thomas
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Stegelmann, Frank
f30069dc-1ed1-41c0-8138-5644934d60fb
Döhner, Konstanze
d8c4c0f5-7715-4a3b-a34d-acd826024088
Chase, A.
a40a09c2-3073-4655-ba0b-a802e34914b5
Cross, Nicholas C.P.
f87650da-b908-4a34-b31b-d62c5f186fe4

Score, Joannah, Hidalgo-Curtis, Claire, Jones, Amy V., Winkelmann, Nils, Skinner, Alison, Ward, Daniel, Zoi, Katerina, Ernst, Thomas, Stegelmann, Frank, Döhner, Konstanze, Chase, A. and Cross, Nicholas C.P. (2012) Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms. Blood, 119 (5), 1208-1213. (doi:10.1182/blood-2011-07-367243). (PMID:22053108)

Record type: Article

Abstract

The polycomb repressive complex 2 (PRC2) is a highly conserved histone H3 lysine 27 methyltransferase that regulates the expression of developmental genes. Inactivating mutations of the catalytic component of PRC2, EZH2, are seen in myeloid disorders. We reasoned that the other two core PRC2 components SUZ12 and EED may also be
mutational targets in these diseases, as well as associated factors such as Jarid2. SUZ12 mutations were identified in 1 of 2 cases with myelodysplastic/myeloproliferative neoplasm (MDS/MPN) with 17q aUPD and 2 of 2 myelofibrosis cases with focal 17q11 deletions. All three were missense mutations affecting the highly conserved VEFS domain. Analysis of a further 146 MDS/MPN cases revealed an additional VEFS domain mutant, yielding a total mutation frequency of 2/148 (1.4%). We did not find mutations of Jarid2 or EED in association with aUPD for chromosome 6p or 11q, respectively, however screening unselected cases identified missense mutations in EED (1/148; 1%) and Jarid2 (3/148; 2%). All three SUZ12 mutations tested and the EED mutation reduced PRC2 histone methyltransferase activity in vitro, thus demonstrating that PRC2 function may be compromised in myeloid disorders by mutation of distinct genes.

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e-pub ahead of print date: 3 November 2011
Published date: 2 February 2012
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 202449
URI: http://eprints.soton.ac.uk/id/eprint/202449
ISSN: 0006-4971
PURE UUID: 46f71d3a-c417-46f4-aae9-a3e4307d801d
ORCID for A. Chase: ORCID iD orcid.org/0000-0001-6617-9953
ORCID for Nicholas C.P. Cross: ORCID iD orcid.org/0000-0001-5481-2555

Catalogue record

Date deposited: 08 Nov 2011 11:20
Last modified: 15 Mar 2024 03:11

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Contributors

Author: Joannah Score
Author: Claire Hidalgo-Curtis
Author: Amy V. Jones
Author: Nils Winkelmann
Author: Alison Skinner
Author: Daniel Ward
Author: Katerina Zoi
Author: Thomas Ernst
Author: Frank Stegelmann
Author: Konstanze Döhner
Author: A. Chase ORCID iD

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