Skip to main content
Dryad logo

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

Citation

Morande, Pablo Elías et al. (2021), AID overexpression leads to aggressive murine CLL and non-Ig mutations that mirror human neoplasms, Dryad, Dataset, https://doi.org/10.5061/dryad.3bk3j9kj2

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.

Methods

Peripheral blood mononuclear cells were collected in a prospective study from patients with confirmed CLL diagnosisAll patients were followed at Hospital Maciel and they provided an informed consent according to the ethical regulations from Uruguay and the Helsinki Declaration. Protocols were approved and conducted in accordance with the Institutional Ethical Committee of the Hospital Maciel and with the principles of the Declaration of Helsinki (CEIHM_ protocol No 28/2017 and 04/2019). Samples were obtained at disease onset for all patients and after 4 years during disease evolution or until treatment in progressive cases. Selection of progressive cases were defined by lymphocyte doubling time <6 months, treatment needed within 3 years, positive mRNA AID expression in PB as well as >2% of CLL B cells with ongoing CSR process, and by the presence of an unmutated IgVH gene profile and positive mRNA of LPL marker.

Usage Notes

Raw data of whole exome sequencing experiments in a pooled dataset.

Funding

ANID, Award: Fondecyt 1180882

ANID, Award: Fondecyt 1180882