DNA Methyltransferase Deficiency Modifies Cancer Susceptibility in Mice Lacking DNA Mismatch Repair

Abstract

We have introduced DNA methyltransferase 1 (Dnmt1) mutations into a mouse strain deficient for the Mlh1 protein to study the interaction between DNA mismatch repair deficiency and DNA methylation. Mice harboring hypomorphic Dnmt1 mutations showed diminished RNA expression and DNA hypomethylation but developed normally and were tumor free. When crossed to Mlh1 ؊/؊ homozygosity, they were less likely to develop the intestinal cancers that normally arise in this tumor-predisposed, mismatch repair-deficient background. However, these same mice developed invasive T-and B-cell lymphomas earlier and at a much higher frequency than their Dnmt1 wild-type littermates. Thus, the reduction of Dnmt1 activity has significant but opposing outcomes in the development of two different tumor types. DNA hypomethylation and mismatch repair deficiency interact to exacerbate lymphomagenesis, while hypomethylation protects against intestinal tumors. The increased lymphomagenesis in Dnmt1 hypomorphic, Mlh1 ؊/؊ mice may be due to a combination of several mechanisms, including elevated mutation rates, increased expression of proviral sequences or proto-oncogenes, and/or enhanced genomic instability. We show that CpG island hypermethylation occurs in the normal intestinal mucosa, is increased in intestinal tumors in Mlh1 ؊/؊ mice, and is reduced in the normal mucosa and tumors of Dnmt1 mutant mice, consistent with a role for Dnmt1-mediated CpG island hypermethylation in intestinal tumorigenesis.

How good are rodent models of carcinogenesis in predicting efficacy in humans? A systematic review and meta-analysis of colon chemoprevention in rats, mice and men

“…Most microsatellites are found in noncoding DNA, but some mutations due to MSI modify genes involved in later stages of carcinogenesis, e.g., transforming growth factor-β receptor II and insulin like growth factor II receptor. Besides mutations, human tumours have a general DNA hypomethylation, but the aberrant hypermethylation of promoter CpG islands leads to transcriptional silencing of key growth-controlling genes and contributes to cancer progression (13). Do tumours in animal models, i.e.…”

MBD2 deficiency does not accelerate p53 mediated lymphomagenesis

“…To address whether the loss of Mbd2 accelerated lymphomagenesis, we intercrossed Mbd2 deficient mice to p53 deficient mice (Sansom and Clarke, 2000). p53 deficiency is the most studied murine model of lymphomagenesis, and unlike MMR deficiency does not induce intestinal tumorigenesis (Trinh et al, 2002). Therefore, the potential confounding problem caused by suppression of tumorigenesis in one organ and acceleration in another was avoided.…”

“…Unlike DNMT1 À/À and DNMT N/N (which are lethal), and DNMT chip/À mice (which are runted), Mbd2 À/À mice are apparently healthy (Li et al, 1992;Hendrich et al, 2001;Trinh et al, 2002;Gaudet et al, 2003). To address whether the loss of Mbd2 accelerated lymphomagenesis, we intercrossed Mbd2 deficient mice to p53 deficient mice (Sansom and Clarke, 2000).…”

“…However, recent murine studies have raised concerns about the effects of proposed antitumour strategies that reduce DNMT1 as global genomic hypomethylation has been shown to induce lymphomas with increased genomic instability Gaudet et al, 2003). The relevance of these finding to treatment of human cancers is uncertain, as the degree of hypomethylation produced by the hypomorphic allele concerned (DNMT1 chip ) is far greater than following treatment with DNA methylation inhibitors such as 5-aza-2 0 -deoxycytidine or other previously reported DNMT1 hypomorphic alleles (DNMT R and DNMT S ) (Trinh et al, 2002;Eden et al, 2003;Gaudet et al, 2003;Yang et al, 2003). However, all of the DNMT1 hypomorphic alleles tested thus far have shown increased lymphomagenesis either alone (DNMT chip/ ) or when crossed to mismatch repair deficient Mlh1 À/À mice (DNMT N and DNMT R ) (Trinh et al, 2002).…”

“…The relevance of these finding to treatment of human cancers is uncertain, as the degree of hypomethylation produced by the hypomorphic allele concerned (DNMT1 chip ) is far greater than following treatment with DNA methylation inhibitors such as 5-aza-2 0 -deoxycytidine or other previously reported DNMT1 hypomorphic alleles (DNMT R and DNMT S ) (Trinh et al, 2002;Eden et al, 2003;Gaudet et al, 2003;Yang et al, 2003). However, all of the DNMT1 hypomorphic alleles tested thus far have shown increased lymphomagenesis either alone (DNMT chip/ ) or when crossed to mismatch repair deficient Mlh1 À/À mice (DNMT N and DNMT R ) (Trinh et al, 2002). Given these adverse effects of DNMT1 inhibition and the strong suppression of intestinal tumorigenesis by Mbd2, we have tested whether inhibition of Mbd2 (which is thought to interpret rather than maintain DNA methylation) also accelerates lymphomagenesis.…”