title: 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 Emicro-Myc transgenic mice, which model aggressive B-cell lymphoma, DNMT3B7 expression increases the frequency of mediastinal lymphomas in Emicro-Myc animals. Emicro-Myc/DNMT3B7 mediastinal lymphomas have more chromosomal rearrangements, increased global DNA methylation levels, and more locus-specific perturbations in DNA methylation patterns compared with Emicro-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.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois 60637-1470, USA.
authors.forename: Mrinal Y
authors.initials: MY
authors.lastname: Shah
authors.forename: Aparna
authors.initials: A
authors.lastname: Vasanthakumar
authors.forename: Natalie Y
authors.initials: NY
authors.lastname: Barnes
authors.forename: Maria E
authors.initials: ME
authors.lastname: Figueroa
authors.forename: Anna
authors.initials: A
authors.lastname: Kamp
authors.forename: Christopher
authors.initials: C
authors.lastname: Hendrick
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Ostler
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Davis
authors.forename: Shang
authors.initials: S
authors.lastname: Lin
authors.forename: John
authors.initials: J
authors.lastname: Anastasi
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
authors.forename: Ivan P
authors.initials: IP
authors.lastname: Moskowitz
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.forename: Peter
authors.initials: P
authors.lastname: Pytel
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Godley
mesh_terms: D000015:Abnormalities, Multiple / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019175:DNA Methylation; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007527:Isoenzymes; D008223:Lymphoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008479:Mediastinal Neoplasms / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D007527:Isoenzymes; D000097584:DNA Methyltransferase 3B