AID overexpression leads to aggressive murine CLL and non-Ig mutations that mirror human neoplasms. - Institut Pasteur Access content directly
Journal Articles Blood Year : 2021

AID overexpression leads to aggressive murine CLL and non-Ig mutations that mirror human neoplasms.

Pablo Elías Morande
  • Function : Author
Xiao-Jie Yan
  • Function : Author
Julieta Haydee Sepulveda-Yanez
  • Function : Author
Noé Seija
  • Function : Author
Maria Elena Marquez
  • Function : Author
Natalia Soledad Sotelo
  • Function : Author
Cecilia Abreu
  • Function : Author
Martina Crispo
  • Function : Author
Gabriel Fernández-Graña
  • Function : Author
Natalia Rego
  • Function : Author
Therence Bois
  • Function : Author
Stephen Patrick Methot
  • Function : Author
Florencia Palacios
  • Function : Author
Victoria Remedi
  • Function : Author
Kanti Rai
  • Function : Author
Javier Marcelo Di Noia
  • Function : Author
Marcelo Alejandro Navarrete
  • Function : Author
Nicholas Chiorazzi
  • Function : Author
Pablo Oppezzo
  • Function : Author

Abstract

Most cancers become more dangerous by the outgrowth of malignant subclones with additional DNA mutations that favor proliferation or survival. Using chronic lymphocytic leukemia (CLL), a disease exemplary of this process, and a model for neoplasms in general, we created transgenic mice overexpressing the enzyme, activation-induced deaminase (AID), whose normal function is to induce DNA mutations in B lymphocytes. AID allows normal B lymphocytes to develop more effective immunoglobulin (Ig)-mediated immunity, but also is able to mutate non-Ig genes, predisposing to cancer. In chronic lymphocytic leukemia (CLL), AID expression correlates with poor prognosis suggesting a role for this enzyme in disease progression. Nevertheless, direct experimental evidence identifying the specific genes that are mutated by AID and indicating that those genes are associated with disease progression is not available. To address this point, we overexpressed Aicda in a murine model of CLL (Em-TCL1). Analyses of TCL1/AID mice demonstrate a role for AID in disease kinetics, CLL-cell proliferation, and the development of cancer-related target mutations with canonical AID signatures in non-Igs genes. Notably, our mouse models can accumulate mutations in the same genes that are mutated in human cancers. Moreover, some of these mutations occur at homologous positions, leading to identical or chemically-similar amino acid substitutions as in human CLL and lymphoma.Together, these findings support a direct link between aberrant AID activity and CLL driver mutations that are then selected for their oncogenic effects, whereby AID promotes aggressiveness in CLL and other B-cell neoplasms.
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Dates and versions

pasteur-03246646 , version 1 (02-06-2021)

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Pablo Elías Morande, Xiao-Jie Yan, Julieta Haydee Sepulveda-Yanez, Noé Seija, Maria Elena Marquez, et al.. AID overexpression leads to aggressive murine CLL and non-Ig mutations that mirror human neoplasms.. Blood, 2021, ⟨10.1182/blood.2020008654⟩. ⟨pasteur-03246646⟩
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