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Letter. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders

Letter. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders
Letter. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders
Abnormalities of chromosome 7q are common in myeloid malignancies, but no specific target genes have yet been identified. Here, we describe the finding of homozygous EZH2 mutations in 9 of 12 individuals with 7q acquired uniparental disomy.

Screening of a total of 614 individuals with myeloid disorders revealed 49 monoallelic or biallelic EZH2 mutations in 42 individuals; the mutations were found most commonly in those with myelodysplastic/myeloproliferative neoplasms (27 out of 219 individuals, or 12%) and in those with myelofibrosis (4 out of 30 individuals, or 13%).

EZH2 encodes the catalytic subunit of the polycomb repressive complex 2 (PRC2), a highly conserved histone H3 lysine 27 (H3K27) methyltransferase that influences stem cell renewal by epigenetic repression of genes involved in cell fate decisions.

EZH2 has oncogenic activity, and its overexpression has previously been causally linked to differentiation blocks in epithelial tumors. Notably, the mutations we identified resulted in premature chain termination or direct abrogation of histone methyltransferase activity, suggesting that EZH2 acts as a tumor suppressor for myeloid malignancies.

1061-4036
722-726
Ernst, Thomas
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Chase, Andrew J.
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Score, Joannah
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Hidalgo-Curtis, Claire E.
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Bryant, Catherine
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Jones, Amy V.
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Waghorn, Katherine
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Zoi, Katerina
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Ross, Fiona M.
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Reiter, Andreas
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Hochhaus, Andreas
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Drexler, Hans G.
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Duncombe, Andrew
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Cervantes, Francisco
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Oscier, David
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Boultwood, Jacqueline
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Grand, Francis H.
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Cross, Nicholas C.P.
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Ernst, Thomas
96c7805b-c900-4545-9f93-1a83d789cb56
Chase, Andrew J.
a40a09c2-3073-4655-ba0b-a802e34914b5
Score, Joannah
ea0db6ef-c17e-4915-b216-ac67c07b26b7
Hidalgo-Curtis, Claire E.
e74087cb-6bc8-49fd-a1b4-80c3750b9369
Bryant, Catherine
d53ab6c9-909d-43cb-84fc-3e197df377f3
Jones, Amy V.
3d296088-a099-45cf-b227-541ff59d800c
Waghorn, Katherine
60a6a26d-556b-41fc-84ee-dab95d63ab68
Zoi, Katerina
0bcb986d-3fef-49dc-b9f8-18daf79e8bfb
Ross, Fiona M.
ec0958f8-b992-4e4a-b7e3-c474600390ba
Reiter, Andreas
ffa23e84-4a13-4cb5-aaf0-3fafe25dbede
Hochhaus, Andreas
b37b9b7d-85ff-455e-994d-fcc2adf94088
Drexler, Hans G.
b6873aed-4cd3-4967-9811-e451d70e8255
Duncombe, Andrew
ce7cb7e9-5aec-4801-ab3c-18b4de474fef
Cervantes, Francisco
f0fca691-dc41-4f9b-b2bd-2a1f2f8d919f
Oscier, David
2e7f0cc1-93e2-441e-857d-7314efae08ec
Boultwood, Jacqueline
653d33fa-0c0a-4a8a-b119-57a6e466b334
Grand, Francis H.
89bd846f-638a-4bda-b8a9-8a1989021b31
Cross, Nicholas C.P.
f87650da-b908-4a34-b31b-d62c5f186fe4

Ernst, Thomas, Chase, Andrew J., Score, Joannah, Hidalgo-Curtis, Claire E., Bryant, Catherine, Jones, Amy V., Waghorn, Katherine, Zoi, Katerina, Ross, Fiona M., Reiter, Andreas, Hochhaus, Andreas, Drexler, Hans G., Duncombe, Andrew, Cervantes, Francisco, Oscier, David, Boultwood, Jacqueline, Grand, Francis H. and Cross, Nicholas C.P. (2010) Letter. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nature Genetics, 42 (8), 722-726. (doi:10.1038/ng.621).

Record type: Article

Abstract

Abnormalities of chromosome 7q are common in myeloid malignancies, but no specific target genes have yet been identified. Here, we describe the finding of homozygous EZH2 mutations in 9 of 12 individuals with 7q acquired uniparental disomy.

Screening of a total of 614 individuals with myeloid disorders revealed 49 monoallelic or biallelic EZH2 mutations in 42 individuals; the mutations were found most commonly in those with myelodysplastic/myeloproliferative neoplasms (27 out of 219 individuals, or 12%) and in those with myelofibrosis (4 out of 30 individuals, or 13%).

EZH2 encodes the catalytic subunit of the polycomb repressive complex 2 (PRC2), a highly conserved histone H3 lysine 27 (H3K27) methyltransferase that influences stem cell renewal by epigenetic repression of genes involved in cell fate decisions.

EZH2 has oncogenic activity, and its overexpression has previously been causally linked to differentiation blocks in epithelial tumors. Notably, the mutations we identified resulted in premature chain termination or direct abrogation of histone methyltransferase activity, suggesting that EZH2 acts as a tumor suppressor for myeloid malignancies.

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Published date: 4 July 2010
Organisations: Human Genetics

Identifiers

Local EPrints ID: 159817
URI: http://eprints.soton.ac.uk/id/eprint/159817
ISSN: 1061-4036
PURE UUID: 13a15e1d-96eb-45c8-b174-87e012d9e468
ORCID for Andrew J. Chase: ORCID iD orcid.org/0000-0001-6617-9953
ORCID for Nicholas C.P. Cross: ORCID iD orcid.org/0000-0001-5481-2555

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Date deposited: 07 Jul 2010 11:00
Last modified: 18 Feb 2021 16:59

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Contributors

Author: Thomas Ernst
Author: Andrew J. Chase ORCID iD
Author: Joannah Score
Author: Claire E. Hidalgo-Curtis
Author: Catherine Bryant
Author: Amy V. Jones
Author: Katherine Waghorn
Author: Katerina Zoi
Author: Fiona M. Ross
Author: Andreas Reiter
Author: Andreas Hochhaus
Author: Hans G. Drexler
Author: Andrew Duncombe
Author: Francisco Cervantes
Author: David Oscier
Author: Jacqueline Boultwood
Author: Francis H. Grand

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