TY - JOUR
T1 - AID overexpression leads to aggressive murine CLL and nonimmunoglobulin mutations that mirror human neoplasms
AU - Morande, Pablo Elías
AU - Yan, Xiao Jie
AU - Sepulveda, Julieta
AU - Seija, Noé
AU - Marquez, María Elena
AU - Sotelo, Natalia
AU - Abreu, Cecilia
AU - Crispo, Martina
AU - Fernández-Graña, Gabriel
AU - Rego, Natalia
AU - Bois, Therence
AU - Methot, Stephen P.
AU - Palacios, Florencia
AU - Remedi, Victoria
AU - Rai, Kanti R.
AU - Buschiazzo, Alejandro
AU - Di Noia, Javier M.
AU - Navarrete, Marcelo A.
AU - Chiorazzi, Nicholas
AU - Oppezzo, Pablo
N1 - Funding Information:
This work was supported, in part, by grants from the Fondo para la Convergencia Estructural del Mercosur (COF 03/11, CSIC I+D_2014, and FCE_1_2011_1_7273 (P.O.); a Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) postdoctoral fellowship and funding from the Agencia Nacional de Investigación e Innovación (ANNI) and Televie (FNRS 7.8506.19) (P.E.M.); Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) grants 1180882 and MAG1895 (M.A.N.); and contributions from The Nash Family Foundation, The Marks Foundation, the Karches Family, and the Jean Walton Fund for Leukemia, Lymphoma, and Myeloma Research (N.C. and K.R.R.).
Funding Information:
The authors thank Davide F. Robbiani and Michel C. Nussenzweig for sharing the Igk-AID Tg mice, Hossein Khiabanian for analytic suggestions, Gimena Dos Santos for helpfulness assistance, and Diego Alvarez from Centro Austral de Tecnolog?a Gen?mica (catg.cl) for his expert bioinformatics advice. This work was supported, in part, by grants from the Fondo para la Convergencia Estructural del Mercosur (COF 03/11, CSIC I+D_2014, and FCE_1_2011_1_7273 (P.O.); a Consejo Nacional de Investigaciones Cient?ficas y T?cnicas (CONICET) postdoctoral fellowship and funding from the Agencia Nacional de Investigaci?n e Innovaci?n (ANNI) and Televie (FNRS 7.8506.19) (P.E.M.); Fondo Nacional de Desarrollo Cient?fico y Tecnol?gico (FONDECYT) grants 1180882 and MAG1895 (M.A.N.); and contributions from The Nash Family Foundation, The Marks Foundation, the Karches Family, and the Jean Walton Fund for Leukemia, Lymphoma, and Myeloma Research (N.C. and K.R.R.).
Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/7/22
Y1 - 2021/7/22
N2 - 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 that exemplifies this process and is a model for neoplasms in general, we created transgenic mice overexpressing the enzyme activation-induced deaminase (AID), which has a normal function of inducing DNA mutations in B lymphocytes. AID not only allows normal B lymphocytes to develop more effective immunoglobulin-mediated immunity, but is also able to mutate nonimmunoglobulin genes, predisposing to cancer. In 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 (Eμ-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 nonimmunoglobulin 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.
AB - 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 that exemplifies this process and is a model for neoplasms in general, we created transgenic mice overexpressing the enzyme activation-induced deaminase (AID), which has a normal function of inducing DNA mutations in B lymphocytes. AID not only allows normal B lymphocytes to develop more effective immunoglobulin-mediated immunity, but is also able to mutate nonimmunoglobulin genes, predisposing to cancer. In 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 (Eμ-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 nonimmunoglobulin 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.
UR - http://www.scopus.com/inward/record.url?scp=85106414151&partnerID=8YFLogxK
UR - http://Link to publication in PubMed
U2 - 10.1182/blood.2020008654
DO - 10.1182/blood.2020008654
M3 - Article
C2 - 33651893
AN - SCOPUS:85106414151
SN - 0006-4971
VL - 138
SP - 246
EP - 258
JO - Blood
JF - Blood
IS - 3
ER -