Requirement of DNMT1 to orchestrate epigenomic reprogramming for NPM-ALK-driven lymphomagenesis.
Animals
Biomarkers, Tumor
Cell Transformation, Neoplastic
/ genetics
Computational Biology
/ methods
DNA (Cytosine-5-)-Methyltransferase 1
/ genetics
DNA Methylation
Disease Models, Animal
Disease Susceptibility
Epigenesis, Genetic
Epigenomics
Gene Deletion
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Humans
Immunohistochemistry
Immunophenotyping
Lymphoma
/ drug therapy
Mice
Mice, Knockout
Mice, Transgenic
Protein-Tyrosine Kinases
/ genetics
STAT3 Transcription Factor
/ metabolism
Signal Transduction
Xenograft Model Antitumor Assays
Journal
Life science alliance
ISSN: 2575-1077
Titre abrégé: Life Sci Alliance
Pays: United States
ID NLM: 101728869
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
25
05
2020
revised:
28
11
2020
accepted:
01
12
2020
entrez:
14
12
2020
pubmed:
15
12
2020
medline:
14
9
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33310759
pii: 4/2/e202000794
doi: 10.26508/lsa.202000794
pmc: PMC7768196
pii:
doi:
Substances chimiques
Biomarkers, Tumor
0
STAT3 Transcription Factor
0
DNA (Cytosine-5-)-Methyltransferase 1
EC 2.1.1.37
DNMT1 protein, human
EC 2.1.1.37
p80(NPM-ALK) protein
EC 2.7.1.-
Protein-Tyrosine Kinases
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Austrian Science Fund FWF
ID : I 4066
Pays : Austria
Organisme : Austrian Science Fund FWF
ID : P 27616
Pays : Austria
Informations de copyright
© 2020 Redl et al.
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