TY - JOUR T1 - Requirement of DNMT1 to orchestrate epigenomic reprogramming for NPM-ALK–driven lymphomagenesis JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202000794 VL - 4 IS - 2 SP - e202000794 AU - Elisa Redl AU - Raheleh Sheibani-Tezerji AU - Crhistian de Jesus Cardona AU - Patricia Hamminger AU - Gerald Timelthaler AU - Melanie Rosalia Hassler AU - Maša Zrimšek AU - Sabine Lagger AU - Thomas Dillinger AU - Lorena Hofbauer AU - Kristina Draganić AU - Andreas Tiefenbacher AU - Michael Kothmayer AU - Charles H Dietz AU - Bernard H Ramsahoye AU - Lukas Kenner AU - Christoph Bock AU - Christian Seiser AU - Wilfried Ellmeier AU - Gabriele Schweikert AU - Gerda Egger Y1 - 2021/02/01 UR - https://www.life-science-alliance.org/content/4/2/e202000794.abstract N2 - 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. ER -