Compagno, MaraWang, QiPighi, ChiaraCheong, Taek-ChinMeng, Fei-LongPoggio, TeresaYeap, Leng-SiewKaraca, ElifBlasco, Rafael B.Langellotto, FernandaAmbrogio, ChiaraVoena, ClaudiaWiestner, AdrianKasar, Siddha N.Brown, JenniferSun, JingWu, CatherineGostissa, MonicaAlt, FrederickChiarle, Roberto2017-11-212017Compagno, M., Q. Wang, C. Pighi, T. Cheong, F. Meng, T. Poggio, L. Yeap, et al. 2017. “Phosphatidylinositol 3-Kinase (PI3K) δ blockade increases genomic instability in B cells.” Nature 542 (7642): 489-493. doi:10.1038/nature21406. http://dx.doi.org/10.1038/nature21406.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34375140Activation-induced cytidine deaminase (AID) is a B-cell specific enzyme that targets immunoglobulin (Ig) genes to initiate class switch recombination (CSR) and somatic hypermutation (SHM)1. Through off-target activity, however, AID has a much broader impact on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in lymphoma development and progression2. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation3. The phosphatidylinositol 3-kinase (PI3K) δ pathway plays a key role in AID regulation by suppressing its expression in B cells4. Novel drugs for leukemia or lymphoma therapy such as idelalisib, duvelisib or ibrutinib block PI3Kδ activity directly or indirectly5–8, potentially affecting AID expression and, consequently, genomic stability in B cells. Here we show that treatment of primary mouse B cells with idelalisib or duvelisib, and to a lesser extent ibrutinib, enhanced the expression of AID and increased somatic hypermutation (SHM) and chromosomal translocation frequency to the Igh locus and to several AID off-target sites. Both these effects were completely abrogated in AID deficient B cells. PI3Kδ inhibitors or ibrutinib increased the formation of AID-dependent tumors in pristane-treated mice. Consistently, PI3Kδ inhibitors enhanced AID expression and translocation frequency to IgH and AID off-target sites in human chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) cell lines, and patients treated with idelalisib, but not ibrutinib, showed increased SHM in AID off-targets. In summary, we show that PI3Kδ or BTK inhibitors increase genomic instability in normal and neoplastic B cells by an AID-dependent mechanism, an effect that should be carefully considered as such inhibitors are administered for years to patients.en-USJournal Article2017-11-2110.1038/nature21406