Requirement of DNMT1 to orchestrate epigenomic reprogramming for NPM-ALK–driven lymphomagenesis

Malignant transformation depends on genetic and epigenetic events that result in a burst of deregulated gene expression and chromatin changes. To dissect the sequence of events in this process, we used a T-cell–specific lymphoma model based on the human oncogenic nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) translocation. We find that transformation of T cells shifts thymic cell populations to an undifferentiated immunophenotype, which occurs only after a period of latency, accompanied by induction of the MYC-NOTCH1 axis and deregulation of key epigenetic enzymes. We discover aberrant DNA methylation patterns, overlapping with regulatory regions, plus a high degree of epigenetic heterogeneity between individual tumors. In addition, ALK-positive tumors show a loss of associated methylation patterns of neighboring CpG sites. Notably, deletion of the maintenance DNA methyltransferase DNMT1 completely abrogates lymphomagenesis in this model, despite oncogenic signaling through NPM-ALK, suggesting that faithful maintenance of tumor-specific methylation through DNMT1 is essential for sustained proliferation and tumorigenesis.

Comparative transcriptional profiling of medullary and cortical thymic cell types identifies epigenetic and transcription factors that uniquely define the mTEClo and cTEC lineages.

The thymus is a key site of immunological activity, with a medulla and cortex. Epithelial cells within the medulla and cortex play important roles in these immunological processes, including positive and negative selection. In this analysis we compared the transcriptomes of mTEClo and cTEC (5). We present a series of epigenetic molecules and transcription factors that uniquely define mTEClo and cTEC, representing the major transcriptional differences between these two cell types of the thymus.