<em>TET2</em> Mutations Are Associated with Specific 5-Methylcytosine and 5-Hydroxymethylcytosine Profiles in Patients with Chronic Myelomonocytic Leukemia

<div><p>Chronic myelomonocytic leukemia (CMML) has recently been associated with a high incidence of diverse mutations in genes such as <em>TET2</em> or <em>EZH2</em> that are implicated in epigenetic mechanisms. We have performed genome-wide DNA methylation arrays and mutational analysis of <em>TET2</em>, <em>IDH1</em>, <em>IDH2</em>, <em>EZH2</em> and <em>JAK2</em> 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 <em>TET2</em>, <em>JAK2</em> and <em>EZH2</em> were found in 15 patients (65%), 4 patients (17%) and 1 patient (4%) respectively while no mutations in the <em>IDH1</em> and <em>IDH2</em> genes were identified. Interestingly, patients with wild type <em>TET2</em> clustered separately from patients with <em>TET2</em> 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 <em>TET2</em> mutant CMML as a biologically distinct disease subtype with a different epigenetic profile.</p>