Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

TET2 mutations are associated with specific methylation 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 implicated in epigenetic mechanisms such as TET2 or EZH2. We have performed genome-wide 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 enrichment in a gene network centered in PLC, JNK and ERK, a recently described pathway involved in CMML was found, suggesting the potential role of epigenetics in the regulation of these pathways. Mutations of TET2, JAK2 and EZH2 were found in 15 patients (65.2%), 4 patients (16.6%) and 1 patient (4.1%) 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 the presence of altered karyotypes a known prognostic factor in CMML. 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. 24 samples of CMML patients, 4 healthy donor Peripheral Blood samples and 4 healthy donor Bone Marror samples

ORGANISM(S): Homo sapiens

SUBMITTER: Xabier Agirre

PROVIDER: E-GEOD-31600 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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

Pérez Cristina C Martínez-Calle Nicolas N Martín-Subero José Ignacio JI Segura Victor V Delabesse Eric E Fernandez-Mercado Marta M Garate Leire L Alvarez Sara S Rifon José J Varea Sara S Boultwood Jacqueline J Wainscoat James S JS Cruz Cigudosa Juan J Calasanz María José MJ Cross Nicholas C P NC Prósper Felipe F Agirre Xabier X

PloS one 20120206 2

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 a ...[more]

PMID: 22328940

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Project description:Primary mielofibrosis (PMF) is a rare chronic myeloproliferative disorder characterized by the accumulation of abnormal megakaryocytes (Mks) in the bone marrow (BM), variable degrees of BM fibrosis, osteosclerosis and angiogenesis, immature myeloid and erythroid cells, and tear-drop erythrocytes in the peripheral blood (PB), and extramedullary hematopoiesis. The identification of the JAK2V617F mutation represented a seminal discovery in the field of Philadelphia-chromosome–negative chronic myeloproliferative neoplasms (MPNs), providing clues to the pathogenesis, prompting a revision of the diagnostic criteria, and culminating in the development of clinical trials with JAK2 (and JAK1) inhibitors. The JAK2V617F mutation occurs in almost all patients with polycythemia vera (PV) and in 50%-70% of those with essential thrombocythemia (ET) and primary myelofibrosis (PMF). Soon after the identification of the JAK2V617F mutation, mutations in JAK2 exon 12 were described in rare patients with JAK2V617F-negative PV and mutations in MPL were reported in 5%-10% of ET or PMF subjects. The complexity of the molecular pathogenesis of MPNs is reinforced by discovery of additional mutations in TET2, ASXL1, CBL, IDH1/IDH2, EZH2 and IKZF1. These mutations are detected in a minority of patients at different phases of the disorder, including leukemic transformation, and are variably associated each other and with JAK2 or MPL mutations. In order to better characterize biological differences between mutated and wild-type PMF cell populations we performed a gene expression profiling on 9 samples carrying at least one mutation in ASXL1, SRSF2 or EZH2 genes and 11 wild-type samples using the Affymetrix GeneChip technology. After data preprocessing and filtering a supervised analysis approach was used to define a gene expression signature for mutated samples. PMF samples carrying at least one mutation in ASXL1, SRSF2 or EZH2 genes exhibit a specific molecular signature as compared with WT samples. Gene expression profile (GEP) of CD34+ cells from 20 PMF patients (1 replicate for each sample). In particular, GEP was performed on 9 samples carrying at least one mutation in ASXL1, SRSF2 or EZH2 genes and 11 wild-type samples.

Dataset Information

TET2 mutations are associated with specific methylation profiles in patients with Chronic Myelomonocytic Leukemia

Publications

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

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