RT Journal Article
SR Electronic
T1 Requirement of DNMT1 to orchestrate epigenomic reprogramming for NPM-ALK–driven lymphomagenesis
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202000794
DO 10.26508/lsa.202000794
VO 4
IS 2
A1 Elisa Redl
A1 Raheleh Sheibani-Tezerji
A1 Crhistian de Jesus Cardona
A1 Patricia Hamminger
A1 Gerald Timelthaler
A1 Melanie Rosalia Hassler
A1 Maša Zrimšek
A1 Sabine Lagger
A1 Thomas Dillinger
A1 Lorena Hofbauer
A1 Kristina Draganić
A1 Andreas Tiefenbacher
A1 Michael Kothmayer
A1 Charles H Dietz
A1 Bernard H Ramsahoye
A1 Lukas Kenner
A1 Christoph Bock
A1 Christian Seiser
A1 Wilfried Ellmeier
A1 Gabriele Schweikert
A1 Gerda Egger
YR 2021
UL https://www.life-science-alliance.org/content/4/2/e202000794.abstract
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.