DNMT3B7, a Truncated DNMT3B Isoform Expressed in Human Tumors, Disrupts Embryonic Development and Accelerates Lymphomagenesis

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 COOH-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 mice 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 locusspecific perturbations in DNA methylation patterns compared with 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 redistribution of DNA methylation characterizing virtually every human tumor.

Fundamental differences in promoter CpG island DNA hypermethylation between human cancer and genetically engineered mouse models of cancer

“…A separate study in Eµ-Myc mice demonstrated a modest increase in DNA methylation by transgenic expression of DNMT3B7, a truncated isoform of DNA methyltransferase 3B that has been found in human cancer cells. 32 This finding is not cancer-specific, however, since an increase in promoter CpG island DNA methylation was observed by ectopic expression of mouse Dnmt3b in normal mouse colon cells. 33 Mouse cells are capable of obtaining extensive promoter CpG island DNA hypermethylation when they are immortalized, as recently shown 29 and in this study.…”

Gene silencing of EREG mediated by DNA methylation and histone modification in human gastric cancers

“…26,27 DNMT3b is directly associated with many human diseases including cancer. 28,29 For example, upregulation of DNMT3b expression is observed in sporadic breast carcinoma and acute myeloid leukemia while DNMT1 and DNMT3a levels are reduced. 30 DNMT3b is also overexpressed and linked to the CpG island methylator phenotype in colon cancer.…”

The role of aberrant DNMT3Bs in tumor progression – a review

“…In the study mentioned previously, Ostler and colleagues noted the presence of DNMT3B7 in several different cancer cell lines [14] . Shah and colleagues investigated this in vivo [18] . First, two lines of transgenic mice that express DNMT3B7 were constructed and embryonic developmental effects were observed.…”

“…First, two lines of transgenic mice that express DNMT3B7 were constructed and embryonic developmental effects were observed. Clear developmental abnormalities were noted including craniofacial, cardiac, and immune defects [18] . These results highlight the importance of proper methylation and subsequent gene silencing and activation during embryogenesis.…”