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Attenuating homologous recombination stimulates an AID-induced antileukemic effect

Activation-induced cytidine deaminase (AID) is critical in normal B cells to initiate somatic hypermutation and immunoglobulin class switch recombination. Accumulating evidence suggests that AID is also prooncogenic, inducing cancer-promoting mutations or chromosome rearrangements. In this context,...

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Detalles Bibliográficos
Autores principales: Lamont, Kristin R., Hasham, Muneer G., Donghia, Nina M., Branca, Jane, Chavaree, Margaret, Chase, Betsy, Breggia, Anne, Hedlund, Jacquelyn, Emery, Ivette, Cavallo, Francesca, Jasin, Maria, Rüter, Jens, Mills, Kevin D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646491/
https://www.ncbi.nlm.nih.gov/pubmed/23589568
http://dx.doi.org/10.1084/jem.20121258
Descripción
Sumario:Activation-induced cytidine deaminase (AID) is critical in normal B cells to initiate somatic hypermutation and immunoglobulin class switch recombination. Accumulating evidence suggests that AID is also prooncogenic, inducing cancer-promoting mutations or chromosome rearrangements. In this context, we find that AID is expressed in >40% of primary human chronic lymphocytic leukemia (CLL) cases, consistent with other reports. Using a combination of human B lymphoid leukemia cells and mouse models, we now show that AID expression can be harnessed for antileukemic effect, after inhibition of the RAD51 homologous recombination (HR) factor with 4,4′-diisothiocyanatostilbene-2-2′-disulfonic acid (DIDS). As a proof of principle, we show that DIDS treatment inhibits repair of AID-initiated DNA breaks, induces apoptosis, and promotes cytotoxicity preferentially in AID-expressing human CLL. This reveals a novel antineoplastic role of AID that can be triggered by inhibition of HR, suggesting a potential new paradigm to treat AID-expressing tumors. Given the growing list of tumor types with aberrant AID expression, this novel therapeutic approach has potential to impact a significant patient population.