Redl, E; Sheibani-Tezerji, R; Cardona, CJ; Hamminger, P; Timelthaler, G; Hassler, MR; Zrimšek, M; Lagger, S; Dillinger, T; Hofbauer, L; Draganić, K; Tiefenbacher, A; Kothmayer, M; Dietz, CH; Ramsahoye, BH; Kenner, L; Bock, C; Seiser, C; Ellmeier, W; Schweikert, G; Egger, G
Requirement of DNMT1 to orchestrate epigenomic reprogramming for NPM-ALK-driven lymphomagenesis.
Life Sci Alliance. 2021; 4(2):e202000794
Autor/innen der Vetmeduni Vienna:
Institut für Pathologie, Abteilung für Labortierpathologie
- 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.© 2020 Redl et al.