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

Elisa Redl, Raheleh Sheibani-Tezerji, Crhistian de Jesus Cardona, Patricia Hamminger, Gerald Timelthaler, Melanie Rosalia Hassler, Maša Zrimšek, Sabine Lagger, Thomas Dillinger, Lorena Hofbauer, Kristina Draganić, Andreas Tiefenbacher, Michael Kothmayer, Charles H. Dietz, Bernard H. Ramsahoye, Lukas Kenner, Christoph Bock, Christian Seiser, Wilfried Ellmeier, Gabriele SchweikertGerda Egger

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Abstract

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.

Original languageEnglish
Article numbere202000794
Number of pages22
JournalLife Science Alliance
Volume4
Issue number2
Early online date11 Dec 2020
DOIs
Publication statusPublished - Feb 2021

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