AID and TET2 co-operation modulates FANCA expression by active demethylation in diffuse large B cell lymphoma

Clin Exp Immunol. 2019 Feb;195(2):190-201. doi: 10.1111/cei.13227. Epub 2018 Nov 13.

Abstract

Diffuse large B cell lymphoma (DLBCL) is traced to a mature B malignance carrying abnormal activation-induced cytidine deaminase (AID) expression. AID activity initially focuses on deamination of cytidine to uracil to generate somatic hypermutation and class-switch recombination of the immunoglobulin (Ig), but recently it has been implicated in DNA demethylation of genes required for B cell development and proliferation in the germinal centre (GC). However, whether AID activity on mutation or demethylation of genes involves oncogenesis of DLBCL has not been well characterized. Our data demonstrate that the proto-oncogene Fanconi anaemia complementation group A (FANCA) is highly expressed in DLBCL patients and cell lines, respectively. AID recruits demethylation enzyme ten eleven translocation family member (TET2) to bind the FANCA promoter. As a result, FANCA is demethylated and its expression increases in DLBCL. On the basis of our findings, we have developed a new therapeutic strategy to significantly inhibit DLBCL cell growth by combination of the proteasome inhibitor bortezomib with AID and TET2 depletion. These findings support a novel mechanism that AID has a crucial role in active demethylation for oncogene activation in DLBCL.

Keywords: 10-11 translocation-2; Fanconi anaemia complementation group A; activation-induced cytidine deaminase; active demethylation; diffuse large B cell lymphoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • B-Lymphocytes / metabolism
  • Bortezomib / pharmacology
  • CRISPR-Cas Systems
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / metabolism
  • Cytidine Deaminase / genetics
  • Cytidine Deaminase / metabolism*
  • DNA Demethylation*
  • DNA-Binding Proteins / metabolism*
  • Dioxygenases
  • Disease Models, Animal
  • Fanconi Anemia Complementation Group A Protein / genetics*
  • Fanconi Anemia Complementation Group A Protein / metabolism
  • Gene Expression Regulation / genetics
  • Gene Knockout Techniques
  • Humans
  • Immunoglobulin Class Switching / genetics
  • Lymphoma, Large B-Cell, Diffuse / drug therapy*
  • Lymphoma, Large B-Cell, Diffuse / immunology
  • Lymphoma, Large B-Cell, Diffuse / pathology*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins / metabolism*
  • Somatic Hypermutation, Immunoglobulin / genetics

Substances

  • Antineoplastic Agents
  • DNA-Binding Proteins
  • FANCA protein, human
  • Fanconi Anemia Complementation Group A Protein
  • MAS1 protein, human
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • Bortezomib
  • Dioxygenases
  • TET2 protein, human
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase