1. ¹Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA
2. ²University of Chicago Cancer Research Center, University of Chicago, Chicago, IL, USA

Correspondence: Dr LA Godley, Section of Hematology/Oncology, University of Chicago, 5841 S. Maryland Ave., MC 2115, Chicago, IL 60637, USA. E-mail: lgodley@medicine.bsd.uchicago.edu

³Current address: Department of Biology, Elmhurst College, 190 Prospect Ave., Elmhurst, IL 60126, USA.

Received 30 November 2006; Revised 17 January 2007; Accepted 17 January 2007; Published online 12 March 2007.

Abstract

Cancer cells display an altered distribution of DNA methylation relative to normal cells. Certain tumor suppressor gene promoters are hypermethylated and transcriptionally inactivated, whereas repetitive DNA is hypomethylated and transcriptionally active. Little is understood about how the abnormal DNA methylation patterns of cancer cells are established and maintained. Here, we identify over 20 DNMT3B transcripts from many cancer cell lines and primary acute leukemia cells that contain aberrant splicing at the 5' end of the gene, encoding truncated proteins lacking the C-terminal catalytic domain. Many of these aberrant transcripts retain intron sequences. Although the aberrant transcripts represent a minority of the DNMT3B transcripts present, Western blot analysis demonstrates truncated DNMT3B isoforms in the nuclear protein extracts of cancer cells. To test if expression of a truncated DNMT3B protein could alter the DNA methylation patterns within cells, we expressed DNMT3B7, the most frequently expressed aberrant transcript, in 293 cells. DNMT3B7-expressing 293 cells have altered gene expression as identified by microarray analysis. Some of these changes in gene expression correlate with altered DNA methylation of corresponding CpG islands. These results suggest that truncated DNMT3B proteins could play a role in the abnormal distribution of DNA methylation found in cancer cells.