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Article Dans Une Revue Blood Année : 2021

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

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

Résumé

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 et 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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