Abstract
Epigenetic changes are among the most common alterations observed in cancer cells, yet the mechanism by which cancer cells acquire and maintain abnormal DNA methylation patterns is not understood. Cancer cells have an altered distribution of DNA methylation and express aberrant
DNA methyltransferase 3B
transcripts, which encode truncated proteins, some of which lack the C-terminal catalytic domain. To test if a truncated DNMT3B isoform disrupts DNA methylation
in vivo
, we constructed two lines of transgenic mice expressing
DNMT3B7
, a truncated DNMT3B isoform commonly found in cancer cells.
DNMT3B7
transgenic mice exhibit altered embryonic development, including lymphopenia, craniofacial abnormalities, and cardiac defects, similar to
Dnmt3b
-deficient animals, but rarely develop cancer. However, when
DNMT3B7
transgenic are bred with
Eμ-Myc
transgenic mice, which model aggressive B cell lymphoma, DNMT3B7 expression increases the frequency of mediastinal lymphomas in
Eμ-Myc
animals.
Eμ-Myc/DNMT3B7
mediastinal lymphomas have more chromosomal rearrangements, increased global DNA methylation levels, and more locus-specific perturbations in DNA methylation patterns compared to
Eμ-Myc
lymphomas. These data represent the first
in vivo
modeling of cancer-associated DNA methylation changes and suggest that truncated DNMT3B isoforms contribute to the re-distribution of DNA methylation characterizing virtually every human tumor.
