Attenuating homologous recombination stimulates an AID-induced antileukemic effect.
4, 4'-Diisothiocyanostilbene-2, 2'-Disulfonic Acid, Active Transport, Cell Nucleus, Animals, B-Lymphocytes, Cell Death, Cell Line, Transformed, Cell Line, Tumor, Cell Nucleus, Cytidine Deaminase, DNA Breaks, Double-Stranded, DNA Repair, Gene Expression Regulation, Leukemic, Histones, Homologous Recombination, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Mice, Rad51 Recombinase, Radiation, Ionizing
J Exp Med 2013 May 6; 210(5):1021-1033.
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. J Exp Med 2013 May 6; 210(5):1021-1033.
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; and Mills, Kevin D., "Attenuating homologous recombination stimulates an AID-induced antileukemic effect." (2013). Faculty Research 2013. 42.