DNA methylation profile in chronic myelomonocytic leukemia associates with distinct clinical, biological and genetic features

Abstract

Chromosomal abnormalities are detected in 20-30% of patients with chronic myelomonocytic leukemia (CMML) and correlate with prognosis. On the mutation level, disruptive alterations are particularly frequent in chromatin regulatory genes. However, little is known about the consequential alterations in the epigenetic marking of the genome. Here, we report the analysis of genomic DNA methylation patterns of 64 CMML patients and 10 healthy controls, using a DNA methylation microarray focused on promoter regions. Differential methylation analysis between patients and controls allowed us to identify abnormalities in DNA methylation, including hypermethylation of specific genes and large genome regions with aberrant DNA methylation. Unsupervised hierarchical cluster analysis identified two main clusters that associated with the clinical, biological, and genetic features of patients. Group 1 was enriched in patients with adverse clinical and biological characteristics and poorer overall and progression-free survival. In addition, significant differences in DNA methylation were observed between patients with low risk and intermediate/high risk karyotypes and between TET2 mutant and wild type patients. Taken together, our results demonstrate that altered DNA methylation patterns reflect the CMML disease state and allow to identify patient groups with distinct clinical features.

Keywords: Chronic myelomonocytic leukemia; DNA methylation; TET2; hypermethylation; prognosis.

Figure 1.

Hierarchical clustering according to DNA methylation in CMML distinguishes two main clusters. Heatmap showing the most variable (>0.4, P < 0.05) differentially methylated probes across the series of CMML patients. Each row represents a single probe and each column corresponds to a separate patient. Each probe has been normalized by the mean β-value in all samples and the color in the heatmap represents the scaled methylation value. Below is represented in color-code the distribution of the clinical features from the patients (WHO classification, FAB classification, AML progression, CPSS risk groups, and cytogenetic features and gene mutations). White gaps represent missing data. AML: acute myeloid leukemia; CPSS: CMML specific prognostic scoring system; FAB: French-American-British; Int: intermediate; WHO: World Health Organization.

Figure 2.

Kaplan-Meier survival curves in CMML patients. (A) Overall survival (OS) and progression free survival (PFS) curves according to the two groups identified by hierarchical clustering. (B) OS and PFS curves according to BCL2 DNA methylation levels.

Figure 3.

Differential methylation between CMML patients displaying distinct molecular and cytogenetic features. The bar plot shows the number of probes differentially methylated (P<0.05) between groups of patients characterized by different molecular features (presence vs. absence of specific gene mutations) and cytogenetic [intermediate/high risk karyotype (IHR-K) vs. low risk karyotype (LR-K)].