Dnmt3a Is a Haploinsufficient Tumor Suppressor in CD8+ Peripheral T Cell Lymphoma

Abstract

DNA methyltransferase 3A (DNMT3A) is an enzyme involved in DNA methylation that is frequently mutated in human hematologic malignancies. We have previously shown that inactivation of Dnmt3a in hematopoietic cells results in chronic lymphocytic leukemia in mice. Here we show that 12% of Dnmt3a-deficient mice develop CD8+ mature peripheral T cell lymphomas (PTCL) and 29% of mice are affected by both diseases. 10% of Dnmt3a+/- mice develop lymphomas, suggesting that Dnmt3a is a haploinsufficient tumor suppressor in PTCL. DNA methylation was deregulated genome-wide with 10-fold more hypo- than hypermethylated promoters and enhancers, demonstrating that hypomethylation is a major event in the development of PTCL. Hypomethylated promoters were enriched for binding sites of transcription factors AML1, NF-κB and OCT1, implying the transcription factors potential involvement in Dnmt3a-associated methylation. Whereas 71 hypomethylated genes showed an increased expression in PTCL, only 3 hypermethylated genes were silenced, suggesting that cancer-specific hypomethylation has broader effects on the transcriptome of cancer cells than hypermethylation. Interestingly, transcriptomes of Dnmt3a+/- and Dnmt3aΔ/Δ lymphomas were largely conserved and significantly overlapped with those of human tumors. Importantly, we observed downregulation of tumor suppressor p53 in Dnmt3a+/- and Dnmt3aΔ/Δ lymphomas as well as in pre-tumor thymocytes from 9 months old but not 6 weeks old Dnmt3a+/- tumor-free mice, suggesting that p53 downregulation is chronologically an intermediate event in tumorigenesis. Decrease in p53 is likely an important event in tumorigenesis because its overexpression inhibited proliferation in mouse PTCL cell lines, suggesting that low levels of p53 are important for tumor maintenance. Altogether, our data link the haploinsufficient tumor suppressor function of Dnmt3a in the prevention of mouse mature CD8+ PTCL indirectly to a bona fide tumor suppressor of T cell malignancies p53.

Catalytically inactive Dnmt3b rescues mouse embryonic development by accessory and repressive functions

“…To generate conventional Dnmt3b knockout allele, we used approach described previously 21,44,45 utilizing Dnmt3b 2loxP mice obtained from E. Li (Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA). we generated Dnmt3a −/− ;Dnmt3b −/− cell line previously 20 .…”

Epigenetic alterations and advancement of treatment in peripheral T-cell lymphoma

“…Staci L. Haney et al suggested that Dnmt3a is a haploinsufficient tumour suppressor in CD8 + peripheral T-cell lymphoma. Decreased expression of DNMT3A is related to the downregulation of the tumour suppressor p53, which may also contribute to the pathogenesis of CD8 + PTCL [ 114 ].…”

DNA methyltransferases and their roles in tumorigenesis

“…Furthermore, the ectopic introduction of c-Kit variants into a Dnmt3a-deficient background produces acute leukemia [43]. Moreover, DNMT3A inactivation leads to the progression of peripheral T cell lymphoma (PTCL) and lung tumors, thus indicating that DNMT3A may act as a tumor-suppressor gene [44, 45]. Studies have also shown that DNMT3B acts as a tumor suppressor in Myc-induced lymphomas and MLL-AF9-driven AML [46].…”