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 Schweikert; Gerda Egger

doi:10.26508/lsa.202000794

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 (Lead / Corresponding author)

Computational Biology

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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 language	English
Article number	e202000794
Number of pages	22
Journal	Life Science Alliance
Volume	4
Issue number	2
Early online date	11 Dec 2020
DOIs	https://doi.org/10.26508/lsa.202000794
Publication status	Published - Feb 2021

ASJC Scopus subject areas

Ecology
Biochemistry, Genetics and Molecular Biology (miscellaneous)
Plant Science
Health, Toxicology and Mutagenesis

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10.26508/lsa.202000794Licence: CC BY

Final Published VersionFinal published version, 5.31 MBLicence: CC BY

Cite this

Redl, E., Sheibani-Tezerji, R., Cardona, C. D. J., Hamminger, P., Timelthaler, G., Hassler, M. R., Zrimšek, M., Lagger, S., Dillinger, T., Hofbauer, L., Draganić, K., Tiefenbacher, A., Kothmayer, M., Dietz, C. H., Ramsahoye, B. H., Kenner, L., Bock, C., Seiser, C., Ellmeier, W., ... Egger, G. (2021). Requirement of DNMT1 to orchestrate epigenomic reprogramming for NPM-ALK-driven lymphomagenesis. Life Science Alliance, 4(2), Article e202000794. https://doi.org/10.26508/lsa.202000794

@article{4e7d198fa5cd4ea3a86b680c87788fa7,

title = "Requirement of DNMT1 to orchestrate epigenomic reprogramming for NPM-ALK-driven lymphomagenesis",

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.",

author = "Elisa Redl and Raheleh Sheibani-Tezerji and Cardona, {Crhistian de Jesus} and Patricia Hamminger and Gerald Timelthaler and Hassler, {Melanie Rosalia} and Ma{\v s}a Zrim{\v s}ek and Sabine Lagger and Thomas Dillinger and Lorena Hofbauer and Kristina Dragani{\'c} and Andreas Tiefenbacher and Michael Kothmayer and Dietz, {Charles H.} and Ramsahoye, {Bernard H.} and Lukas Kenner and Christoph Bock and Christian Seiser and Wilfried Ellmeier and Gabriele Schweikert and Gerda Egger",

note = "Funding for this research was provided by: Austrian Science Foundation (FWF) projects (P27616 and I4066); BMBF-funded de.NBI Cloud (031A537B, 031A533A, 031A538A, 031A533B, 031A535A, 031A537C, 031A534A, 031A532B); International Max Planck Research School for Intelligent Systems.",

year = "2021",

month = feb,

doi = "10.26508/lsa.202000794",

language = "English",

volume = "4",

journal = "Life Science Alliance",

issn = "2575-1077",

publisher = "EMBO Press",

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Redl, E, Sheibani-Tezerji, R, Cardona, CDJ, 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 2021, 'Requirement of DNMT1 to orchestrate epigenomic reprogramming for NPM-ALK-driven lymphomagenesis', Life Science Alliance, vol. 4, no. 2, e202000794. https://doi.org/10.26508/lsa.202000794

TY - JOUR

T1 - Requirement of DNMT1 to orchestrate epigenomic reprogramming for NPM-ALK-driven lymphomagenesis

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

N1 - Funding for this research was provided by: Austrian Science Foundation (FWF) projects (P27616 and I4066); BMBF-funded de.NBI Cloud (031A537B, 031A533A, 031A538A, 031A533B, 031A535A, 031A537C, 031A534A, 031A532B); International Max Planck Research School for Intelligent Systems.

PY - 2021/2

Y1 - 2021/2

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.

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.

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U2 - 10.26508/lsa.202000794

DO - 10.26508/lsa.202000794

M3 - Article

C2 - 33310759

SN - 2575-1077

VL - 4

JO - Life Science Alliance

JF - Life Science Alliance

IS - 2

M1 - e202000794

ER -

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

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Novel Machine Learning Techniques to Elucidate Function and Dynamics of Epigenomic Mechanisms

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

Abstract

ASJC Scopus subject areas

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Novel Machine Learning Techniques to Elucidate Function and Dynamics of Epigenomic Mechanisms

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