title: TET2 mutations are associated with specific 5-methylcytosine and 5-hydroxymethylcytosine profiles in patients with chronic myelomonocytic leukemia.
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 been recently 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.
authors.affiliation: Laboratory of Myeloproliferative Syndromes, Oncology Area, University of Navarra, Pamplona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Pérez
authors.forename: Nicolas
authors.initials: N
authors.lastname: Martínez-Calle
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Martín-Subero
authors.forename: Victor
authors.initials: V
authors.lastname: Segura
authors.forename: Eric
authors.initials: E
authors.lastname: Delabesse
authors.forename: Marta
authors.initials: M
authors.lastname: Fernandez-Mercado
authors.forename: Leire
authors.initials: L
authors.lastname: Garate
authors.forename: Sara
authors.initials: S
authors.lastname: Alvarez
authors.forename: José
authors.initials: J
authors.lastname: Rifon
authors.forename: Sara
authors.initials: S
authors.lastname: Varea
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Boultwood
authors.forename: James S
authors.initials: JS
authors.lastname: Wainscoat
authors.forename: Juan
authors.initials: J
authors.lastname: Cruz Cigudosa
authors.forename: María José
authors.initials: MJ
authors.lastname: Calasanz
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
authors.forename: Felipe
authors.initials: F
authors.lastname: Prósper
authors.forename: Xabier
authors.initials: X
authors.lastname: Agirre
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D019295:Computational Biology; D003596:Cytosine / Q000031:analogs & derivatives; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D000071221:Enhancer of Zeste Homolog 2 Protein; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D053614:Janus Kinase 2 / Q000235:genetics; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D063151:Polycomb Repressive Complex 2; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C507924:JAK2 protein, human; D053614:Janus Kinase 2