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TET2 mutations are associated with specific 5-methylcytosine and 5-hydroxymethylcytosine profiles in patients with chronic myelomonocytic leukemia

TET2 mutations are associated with specific 5-methylcytosine and 5-hydroxymethylcytosine profiles in patients with chronic myelomonocytic leukemia
TET2 mutations are associated with specific 5-methylcytosine and 5-hydroxymethylcytosine profiles in patients with chronic myelomonocytic leukemia
Chronic myelomonocytic leukemia (CMML) has recently been associated with a high incidence of diverse mutations in genes such as TET2 or EZH2 that are implicated in epigenetic mechanisms. We have performed genome-wide DNA methylation arrays and mutational analysis of TET2, IDH1, IDH2, EZH2 and JAK2 in a group of 24 patients with CMML. 249 genes were differentially methylated between CMML patients and controls. Using Ingenuity pathway analysis, we identified enrichment in a gene network centered around PLC, JNK and ERK suggesting that these pathways, whose deregulation has beenrecently described in CMML, are affected by epigenetic mechanisms. Mutations of TET2, JAK2 and EZH2 were found in 15 patients (65%), 4 patients (17%) and 1 patient (4%) respectively while no mutations in the IDH1 and IDH2 genes were identified. Interestingly, patients with wild type TET2 clustered separately from patients with TET2 mutations, showed a higher degree of hypermethylation and were associated with higher risk karyotypes. Our results demonstrate the presence of aberrant DNA methylation in CMML and identifies TET2 mutant CMML as a biologically distinct disease subtype with a different epigenetic profile.

1932-6203
e31605
Ballestar, Esteban
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Pérez, Cristina
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Martínez-Calle, Nicolas
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Martín-Subero, José Ignacio
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Segura, Victor
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Delabesse, Eric
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Fernandez-Mercado, Marta
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Garate, Leire
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Alvarez, Sara
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Rifon, José
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Varea, Sara
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Boultwood, Jacqueline
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Wainscoat, James S.
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Cigudosa, Juan Cruz
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Calasanz, María José
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Cross, Nicholas C. P.
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Prósper, Felipe
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Agirre, Xabier
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Ballestar, Esteban
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Pérez, Cristina
233d77a1-1cf6-4c08-86ef-41b5e3893035
Martínez-Calle, Nicolas
35adf498-6619-4cd6-83b8-b927033a2e40
Martín-Subero, José Ignacio
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Segura, Victor
ce482e38-ca49-4fa9-8d80-ae92d060cdae
Delabesse, Eric
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Fernandez-Mercado, Marta
a72143b0-30e0-4ff1-bc8b-7ed0ae7dd1e0
Garate, Leire
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Alvarez, Sara
cd209272-1636-43c1-bd60-9b2f11e067f3
Rifon, José
2be8cb17-3ebc-4328-a1d4-a182baf0c231
Varea, Sara
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Boultwood, Jacqueline
653d33fa-0c0a-4a8a-b119-57a6e466b334
Wainscoat, James S.
d7ab3d21-ec29-4315-b32e-08e6fdeb35d3
Cigudosa, Juan Cruz
c73ed857-b203-438d-88d7-a86987aa44b4
Calasanz, María José
12f8745b-30d2-4be4-bfa8-a0feff79bafb
Cross, Nicholas C. P.
f87650da-b908-4a34-b31b-d62c5f186fe4
Prósper, Felipe
542f53af-fa40-4146-b02f-d5bed735fbbc
Agirre, Xabier
85441780-f5a1-451f-8b05-6efd5037da6a

Ballestar, Esteban, Pérez, Cristina, Martínez-Calle, Nicolas, Martín-Subero, José Ignacio, Segura, Victor, Delabesse, Eric, Fernandez-Mercado, Marta, Garate, Leire, Alvarez, Sara, Rifon, José, Varea, Sara, Boultwood, Jacqueline, Wainscoat, James S., Cigudosa, Juan Cruz, Calasanz, María José, Cross, Nicholas C. P., Prósper, Felipe and Agirre, Xabier (2012) TET2 mutations are associated with specific 5-methylcytosine and 5-hydroxymethylcytosine profiles in patients with chronic myelomonocytic leukemia. PLoS ONE, 7 (2), e31605. (doi:10.1371/journal.pone.0031605).

Record type: Article

Abstract

Chronic myelomonocytic leukemia (CMML) has recently been associated with a high incidence of diverse mutations in genes such as TET2 or EZH2 that are implicated in epigenetic mechanisms. We have performed genome-wide DNA methylation arrays and mutational analysis of TET2, IDH1, IDH2, EZH2 and JAK2 in a group of 24 patients with CMML. 249 genes were differentially methylated between CMML patients and controls. Using Ingenuity pathway analysis, we identified enrichment in a gene network centered around PLC, JNK and ERK suggesting that these pathways, whose deregulation has beenrecently described in CMML, are affected by epigenetic mechanisms. Mutations of TET2, JAK2 and EZH2 were found in 15 patients (65%), 4 patients (17%) and 1 patient (4%) respectively while no mutations in the IDH1 and IDH2 genes were identified. Interestingly, patients with wild type TET2 clustered separately from patients with TET2 mutations, showed a higher degree of hypermethylation and were associated with higher risk karyotypes. Our results demonstrate the presence of aberrant DNA methylation in CMML and identifies TET2 mutant CMML as a biologically distinct disease subtype with a different epigenetic profile.

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Published date: 2012
Organisations: Human Development & Health

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Local EPrints ID: 334312
URI: https://eprints.soton.ac.uk/id/eprint/334312
ISSN: 1932-6203
PURE UUID: 6bdb0223-951e-477e-a2bd-f4dd9d78cb8a
ORCID for Nicholas C. P. Cross: ORCID iD orcid.org/0000-0001-5481-2555

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Date deposited: 06 Mar 2012 15:43
Last modified: 12 Nov 2019 01:51

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Contributors

Author: Esteban Ballestar
Author: Cristina Pérez
Author: Nicolas Martínez-Calle
Author: José Ignacio Martín-Subero
Author: Victor Segura
Author: Eric Delabesse
Author: Marta Fernandez-Mercado
Author: Leire Garate
Author: Sara Alvarez
Author: José Rifon
Author: Sara Varea
Author: Jacqueline Boultwood
Author: James S. Wainscoat
Author: Juan Cruz Cigudosa
Author: María José Calasanz
Author: Felipe Prósper
Author: Xabier Agirre

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