PT  - JOURNAL ARTICLE
AU  - Redl, Elisa
AU  - Sheibani-Tezerji, Raheleh
AU  - Cardona, Crhistian de Jesus
AU  - Hamminger, Patricia
AU  - Timelthaler, Gerald
AU  - Hassler, Melanie Rosalia
AU  - Zrimšek, Maša
AU  - Lagger, Sabine
AU  - Dillinger, Thomas
AU  - Hofbauer, Lorena
AU  - Draganić, Kristina
AU  - Tiefenbacher, Andreas
AU  - Kothmayer, Michael
AU  - Dietz, Charles H
AU  - Ramsahoye, Bernard H
AU  - Kenner, Lukas
AU  - Bock, Christoph
AU  - Seiser, Christian
AU  - Ellmeier, Wilfried
AU  - Schweikert, Gabriele
AU  - Egger, Gerda
TI  - Requirement of DNMT1 to orchestrate epigenomic reprogramming for NPM-ALK–driven lymphomagenesis
AID  - 10.26508/lsa.202000794
DP  - 2021 Feb 01
TA  - Life Science Alliance
PG  - e202000794
VI  - 4
IP  - 2
4099  - http://www.life-science-alliance.org/content/4/2/e202000794.short
4100  - http://www.life-science-alliance.org/content/4/2/e202000794.full
SO  - Life Sci. Alliance2021 Feb 01; 4
AB  - 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.