Attenuating homologous recombination stimulates an AID-induced antileukemic effect Journal Article
| Authors: | Lamont, K. R.; Hasham, M. G.; Donghia, N. M.; Branca, J.; Chavaree, M.; Chase, B.; Breggia, A.; Hedlund, J.; Emery, I.; Cavallo, F.; Jasin, M.; Ruter, J.; Mills, K. D. |
| Article Title: | Attenuating homologous recombination stimulates an AID-induced antileukemic effect |
| 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. ©2013 Lamont et al. |
| Keywords: | adult; clinical article; controlled study; protein expression; aged; human cell; genetics; nonhuman; drug targeting; mouse; animal; metabolism; animals; mice; cell death; homologous recombination; dna repair; apoptosis; enzyme inhibition; cell line; animal experiment; animal model; antineoplastic activity; cytotoxicity; drug effect; enzymology; pathology; cell line, tumor; radiation exposure; b lymphocyte; b-lymphocytes; dna strand breakage; gene expression regulation; activation induced cytidine deaminase; cytidine deaminase; drug mechanism; histone; leukemia cell; tumor cell line; ionizing radiation; cell line, transformed; dna breaks, double-stranded; radiation, ionizing; active transport, cell nucleus; double stranded dna break; cell nucleus; chronic lymphatic leukemia; h2afx protein, human; histones; leukemia, lymphocytic, chronic, b-cell; rad51 protein; gene expression regulation, leukemic; rad51 recombinase; aicda (activation induced cytidine deaminase); aicda (activation-induced cytidine deaminase); active transport; 4,4' diisothiocyanatostilbene 2,2' disulfonic acid; 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 210 |
| Issue: | 5 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2013-05-06 |
| Start Page: | 1021 |
| End Page: | 1033 |
| Language: | English |
| DOI: | 10.1084/jem.20121258 |
| PUBMED: | 23589568 |
| PROVIDER: | scopus |
| PMCID: | PMC3646491 |
| DOI/URL: | |
| Notes: | --- - Cited By (since 1996):1 - "Export Date: 25 September 2013" - "CODEN: JEMEA" - "Source: Scopus" |
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