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Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
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Dnmt3b is a haploinsufficient tumor suppressor gene in Myc-induced lymphomagenesis

Aparna Vasanthakumar1, Janet B Lepore, Matthew H Zegarek

  • 1Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.

Blood
|January 15, 2013
PubMed

Insights

Reduced DNA methyltransferase 3B (DNMT3B) dosage accelerates cancer development in mice, indicating DNMT3B acts as a tumor suppressor. Aberrant splicing and haploinsufficiency both impact cancer progression.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Aberrant DNA methylation is a hallmark of human cancers.
  • Abnormal splicing of the DNA methyltransferase 3B (DNMT3B) gene produces truncated proteins, potentially acting as dominant-negative isoforms.
  • The role of DNMT3B dosage in tumorigenesis requires further investigation.

Purpose of the Study:

  • To investigate whether reduced DNMT3B dosage influences cancer development.
  • To compare the effects of DNMT3B haploinsufficiency and a truncated DNMT3B isoform (DNMT3B7) on lymphomagenesis.

Main Methods:

  • Breeding of Dnmt3b(+/-) mice with Eµ-Myc mice, a model for B-cell lymphomas.
  • Analysis of lymphomagenesis acceleration in Eµ-Myc/Dnmt3b(+/-) mice.
  • Comparison of molecular mechanisms underlying changes in tumorigenesis and DNA methylation.

Main Results:

  • Eµ-Myc/Dnmt3b(+/-) mice exhibited significantly accelerated lymphomagenesis compared to Eµ-Myc mice.
  • This acceleration was even greater than in Eµ-Myc mice expressing the DNMT3B7 isoform.
  • Both reduced Dnmt3b dosage and DNMT3B7 expression similarly affected tumorigenesis and DNA hypermethylation, but via distinct molecular pathways.

Conclusions:

  • Dnmt3b functions as a haploinsufficient tumor suppressor gene.
  • Both reduced gene dosage and truncated isoforms of DNMT3B impact cancer progression.
  • Myc-induced lymphomas are sensitive to alterations in DNA methylation, providing insights into epigenetic regulation in cancer.

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