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

Life Sci Alliance. 2020 Dec 11;4(2):e202000794. doi: 10.26508/lsa.202000794. Print 2021 Feb.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism*
  • Computational Biology / methods
  • DNA (Cytosine-5-)-Methyltransferase 1 / genetics
  • DNA (Cytosine-5-)-Methyltransferase 1 / metabolism*
  • 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
  • Lymphoma / etiology*
  • Lymphoma / metabolism*
  • Lymphoma / pathology
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Protein-Tyrosine Kinases / genetics*
  • Protein-Tyrosine Kinases / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • STAT3 Transcription Factor
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNMT1 protein, human
  • p80(NPM-ALK) protein
  • Protein-Tyrosine Kinases