Decreases in different Dnmt3b activities drive distinct development of hematologic malignancies in mice

J Biol Chem. 2021 Jan-Jun:296:100285. doi: 10.1016/j.jbc.2021.100285. Epub 2021 Jan 13.

Abstract

DNA methylation regulates gene transcription and is involved in various physiological processes in mammals, including development and hematopoiesis. It is catalyzed by DNA methyltransferases including Dnmt1, Dnmt3a, and Dnmt3b. For Dnmt3b, its effects on transcription can result from its own DNA methylase activity, the recruitment of other Dnmts to mediate methylation, or transcription repression in a methylation-independent manner. Low-frequency mutations in human DNMT3B are found in hematologic malignancies including cutaneous T-cell lymphomas, hairy cell leukemia, and diffuse large B-cell lymphomas. Moreover, Dnmt3b is a tumor suppressor in oncogene-driven lymphoid and myeloid malignancies in mice. However, it is poorly understood how the different Dnmt3b activities contribute to these outcomes. We modulated Dnmt3b activity in vivo by generating Dnmt3b+/- mice expressing one wild-type allele as well as Dnmt3b+/CI and Dnmt3bCI/CI mice where one or both alleles express catalytically inactive Dnmt3bCI. We show that 43% of Dnmt3b+/- mice developed T-cell lymphomas, chronic lymphocytic leukemia, and myeloproliferation over 18 months, thus resembling phenotypes previously observed in Dnmt3a+/- mice, possibly through regulation of shared target genes. Interestingly, Dnmt3b+/CI and Dnmt3bCI/CI mice survived postnatal development and were affected by B-cell rather than T-cell malignancies with decreased penetrance. Genome-wide hypomethylation, increased expression of oncogenes such as Jdp2, STAT1, and Trip13, and p53 downregulation were major events contributing to Dnmt3b+/- lymphoma development. We conclude that Dnmt3b catalytic activity is critical to prevent B-cell transformation in vivo, whereas accessory and methylation-independent repressive functions are important to prevent T-cell transformation.

Keywords: DNA methylation; Dnmt3b; hematologic malignancies; leukemia; lymphoma.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / genetics
  • ATPases Associated with Diverse Cellular Activities / metabolism
  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • DNA (Cytosine-5-)-Methyltransferases / deficiency
  • DNA (Cytosine-5-)-Methyltransferases / genetics*
  • DNA Methylation
  • DNA Methyltransferase 3B
  • DNA, Neoplasm / genetics
  • DNA, Neoplasm / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Heterozygote
  • Homozygote
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Leukemia, Lymphocytic, Chronic, B-Cell / enzymology
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Lymphoma, B-Cell / enzymology
  • Lymphoma, B-Cell / genetics*
  • Lymphoma, B-Cell / pathology
  • Lymphoma, T-Cell / enzymology
  • Lymphoma, T-Cell / genetics*
  • Lymphoma, T-Cell / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Myeloproliferative Disorders / enzymology
  • Myeloproliferative Disorders / genetics*
  • Myeloproliferative Disorders / pathology
  • Neoplasms, Experimental / enzymology
  • Neoplasms, Experimental / genetics*
  • Neoplasms, Experimental / pathology
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Cell Cycle Proteins
  • DNA, Neoplasm
  • Isoenzymes
  • Jundp2 protein, mouse
  • Repressor Proteins
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Tumor Suppressor Protein p53
  • DNA (Cytosine-5-)-Methyltransferases
  • ATPases Associated with Diverse Cellular Activities
  • Trip13 protein, mouse