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.
MeSH terms
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4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / pharmacology
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Active Transport, Cell Nucleus / drug effects
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Active Transport, Cell Nucleus / radiation effects
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Animals
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B-Lymphocytes / drug effects
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B-Lymphocytes / enzymology
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B-Lymphocytes / pathology
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B-Lymphocytes / radiation effects
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Cell Death / drug effects
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Cell Death / radiation effects
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Cell Line, Transformed
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Cell Line, Tumor
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Cytidine Deaminase / genetics
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Cytidine Deaminase / metabolism*
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DNA Breaks, Double-Stranded / drug effects
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DNA Breaks, Double-Stranded / radiation effects
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DNA Repair / drug effects
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DNA Repair / radiation effects
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Gene Expression Regulation, Leukemic / drug effects
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Gene Expression Regulation, Leukemic / radiation effects
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Histones / metabolism
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Homologous Recombination / drug effects
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Homologous Recombination / genetics*
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Homologous Recombination / radiation effects
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Humans
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Leukemia, Lymphocytic, Chronic, B-Cell / enzymology*
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
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Mice
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Rad51 Recombinase / metabolism
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Radiation, Ionizing
Substances
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H2AX protein, human
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Histones
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Rad51 Recombinase
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AICDA (activation-induced cytidine deaminase)
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Cytidine Deaminase
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4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid