Promoter Hypomethylation and Expression Is Conserved in Mouse Chronic Lymphocytic Leukemia Induced by Decreased or Inactivated Dnmt3a

Cell Rep. 2016 May 10;15(6):1190-201. doi: 10.1016/j.celrep.2016.04.004. Epub 2016 Apr 28.

Abstract

DNA methyltransferase 3a (DNMT3A) catalyzes the formation of 5-methyl-cytosine in mammalian genomic DNA, and it is frequently mutated in human hematologic malignancies. Bi-allelic loss of Dnmt3a in mice results in leukemia and lymphoma, including chronic lymphocytic leukemia (CLL). Here, we investigate whether mono-allelic loss of Dnmt3a is sufficient to induce disease. We show that, by 16 months of age, 65% of Dnmt3a(+/-) mice develop a CLL-like disease, and 15% of mice develop non-malignant myeloproliferation. Genome-wide methylation analysis reveals that reduced Dnmt3a levels induce promoter hypomethylation at similar loci in Dnmt3a(+/-) and Dnmt3a(Δ/Δ) CLL, suggesting that promoters are particularly sensitive to Dnmt3a levels. Gene expression analysis identified 26 hypomethylated and overexpressed genes common to both Dnmt3a(+/-) and Dnmt3a(Δ/Δ) CLL as putative oncogenic drivers. Our data provide evidence that Dnmt3a is a haplo-insufficient tumor suppressor in CLL and highlights the importance of deregulated molecular events in disease pathogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • DNA (Cytosine-5-)-Methyltransferases / deficiency
  • DNA (Cytosine-5-)-Methyltransferases / metabolism*
  • DNA Methylation / genetics*
  • DNA Methyltransferase 3A
  • Gene Expression Regulation, Leukemic*
  • Heterozygote
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / enzymology*
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Mice
  • Promoter Regions, Genetic*
  • Transcription, Genetic
  • Transcriptome / genetics

Substances

  • DNMT3A protein, human
  • Dnmt3a protein, mouse
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methyltransferase 3A