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.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Kristin R
authors.initials: KR
authors.lastname: Lamont
authors.forename: Muneer G
authors.initials: MG
authors.lastname: Hasham
authors.forename: Nina M
authors.initials: NM
authors.lastname: Donghia
authors.forename: Jane
authors.initials: J
authors.lastname: Branca
authors.forename: Margaret
authors.initials: M
authors.lastname: Chavaree
authors.forename: Betsy
authors.initials: B
authors.lastname: Chase
authors.forename: Anne
authors.initials: A
authors.lastname: Breggia
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Hedlund
authors.forename: Ivette
authors.initials: I
authors.lastname: Emery
authors.forename: Francesca
authors.initials: F
authors.lastname: Cavallo
authors.forename: Maria
authors.initials: M
authors.lastname: Jasin
authors.forename: Jens
authors.initials: J
authors.lastname: Rüter
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Mills
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000528:radiation effects; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000528:radiation effects; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000528:radiation effects; D006657:Histones / Q000378:metabolism; D059765:Homologous Recombination / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology* / Q000235:genetics*; D051379:Mice; D051135:Rad51 Recombinase / Q000378:metabolism; D011839:Radiation, Ionizing; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: C468783:H2AX protein, human; D006657:Histones; D051135:Rad51 Recombinase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid