Attenuating homologous recombination stimulates an AID-induced antileukemic effect.
Document Type
Article
Publication Date
5-6-2013
Keywords
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
JAX Source
J Exp Med 2013 May 6; 210(5):1021-1033.
ISSN
1540-9538
PMID
23589568
Abstract
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.
Recommended Citation
Lamont KR,
Hasham MG,
Donghia NM,
Branca J,
Chavaree M,
Chase B,
Breggia A,
Hedlund J,
Emery I,
Cavallo F,
Jasin M,
Rüter J,
Mills KD.
Attenuating homologous recombination stimulates an AID-induced antileukemic effect. J Exp Med 2013 May 6; 210(5):1021-1033.