Abstract
Despite mounting evidence that epigenetic abnormalities play a key role in cancer biology, their contributions to the malignant phenotype remain poorly understood. Here we studied genome-wide DNA methylation in normal B-cell populations and subtypes of B-cell non-Hodgkin lymphoma: follicular lymphoma and diffuse large B-cell lymphomas. These lymphomas display striking and progressive intra-tumor heterogeneity and also inter-patient heterogeneity in their cytosine methylation patterns. Epigenetic heterogeneity is initiated in normal germinal center B-cells, increases markedly with disease aggressiveness, and is associated with unfavorable clinical outcome. Moreover, patterns of abnormal methylation vary depending upon chromosomal regions, gene density and the status of neighboring genes. DNA methylation abnormalities arise via two distinct processes: i) lymphomagenic transcriptional regulators perturb promoter DNA methylation in a target gene-specific manner, and ii) aberrant epigenetic states tend to spread to neighboring promoters in the absence of CTCF insulator binding sites.
Highlights
Follicular lymphomas (FLs) and diffuse large B-cell lymphomas (DLBCLs) are the most common non-Hodgkin lymphomas [1]
DNA methylation heterogeneity is associated with increasing disease aggressiveness We examined the DNA methylation profiles of normal naıve Bcells (NBC, 8 samples), normal germinal center B-cells (NGC, 10 samples), follicular lymphomas (FL, 8 samples), germinal center Blike DLBCLs (GCB, 39 samples), and activated B-like DLBCLs (ABC, 18 samples) (Figure 1A, Methods and Text S1, Module 1; Table S1) using the HELP assay [7] and custom-designed NimbleGen microarrays with probesets representing
Using a phylogenetic clustering approach [12], which arranges samples according to their distance in methylation patterning from that of undifferentiated cells, we found that genome-wide DNA methylation undergoes progressive changes from bone marrow CD34+ hematopoietic progenitor cells to naıve B-cells (NBC) and NGC, FL and DLBCL (Figure 2A)
Summary
Follicular lymphomas (FLs) and diffuse large B-cell lymphomas (DLBCLs) are the most common non-Hodgkin lymphomas [1]. Genetic defects arising as a byproduct of this immunoglobulin affinity maturation process are believed to give rise to FLs and DLBCLs [4]. Consistent with this hypothesis, genomic resequencing studies identified a large number of mutations occurring in FL and DLBCL. Emerging data suggest that epigenetic gene regulation through cytosine methylation is perturbed in FLs and DLBCLs, yet very little is known about how aberrant DNA methylation contributes to the disease phenotype, the genomic features of epigenetic defects in these tumor types, and mechanisms through which these defects occur. We hypothesized that direct comparison of DNA methylation patterning in normal B-cells, FLs and DLBCLs would provide clues about gene deregulation during lymphomagenesis and explain the nature of the different clinical behavior of these lymphoma subtypes
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