In fact, HSP90 inhibitors reduced the levels of anti-dsDNA antibodies and proteinuria, a consequence of antibody deposition in the kidneys in the MRLlpr/lpr mouse model of SLE [47]. levels and isotype switching in immunized mice. HSP90 inhibitors also reduce disease severity in a mouse model of acute B-cell lymphoblastic leukemia in which AID accelerates disease progression. We further show that human AID protein levels are sensitive to HSP90 inhibition in normal and leukemic B cells, and that HSP90 inhibition prevents AID-dependent epithelial to mesenchymal transition in a human breast cancer cell line in vitro. Thus, we provide proof-of-concept that HSP90 inhibitors indirectly target AID in vivo and that PS 48 endogenous human AID is widely sensitive to them, which could have therapeutic applications. exons encoding for IgM for those encoding another isotype [1, 4]. Affinity maturation and isotype switching play important roles in autoimmune diseases and AID can thereby contribute to pathogenesis. AID levels correlate with pathogenic autoantibodies in mouse autoimmune arthritis [5] and MRLlpr/lpr mice, a model of systemic lupus erythematosus (SLE) in which AID function contributes to nephritis [6-8]. Human patients with rheumatoid arthritis and SLE also show higher levels of AID and this is associated to a worst disease [9, 10]. In this context, AID inhibition could be therapeutic but no specific inhibitor is available. AID has oncogenic side PS 48 effects that are intrinsically associated with the mechanisms of SHM and MIF CSR. AID overexpression is oncogenic [11, 12] but normal levels of AID can also mutate and induce chromosomal translocations affecting oncogenes and tumor suppressors [13, 14]. AID is most likely etiological in the GC-derived B-cell neoplasms diffuse large B-cell lymphoma and Burkitts lymphoma (BL) [14, 15]. AID is also expressed in non GC-derived hematological malignancies such as chronic myelogenous leukemia (CML) [16], B-cell acute lymphoblastic leukemia (B-ALL) [17, 18] and, chronic lymphocytic leukemia (CLL) [19-21]. In these leukemia, AID favors disease progression and correlates PS 48 with poorer outcome [16, 17, 22-24]. Hence, also in this context AID inhibition could have therapeutic value [25]. Some human epithelial cancers express AID [26], albeit it only seems to produce substantial numbers of mutations in neoplasms of B-cell origin [27]. Nevertheless, AID could still contribute to the progression of certain epithelial cancers through non-canonical functions such as DNA demethylation and transcriptional regulation [28]. Indeed, low levels of AID expression can influence epigenetic reprograming of pluripotent cells and alter the gene expression profile in human fibroblasts [28, 29]. We have shown that AID is necessary for the cytokine-induced epithelial to mesenchymal transition (EMT) in mammary epithelial cell lines: ZR75.1 breast cancer cells depleted of AID fail to upregulate genes required for the EMT and PS 48 lose metastatic characteristics i.e.: the PS 48 ability to invade and migrate under EMT-inducing conditions [30]. While the mechanism/s of these non-canonical functions of AID are unknown and their biological relevance is controversial, these evidences indicate that AID has at least the capacity to influence gene expression in certain settings [28]. Thus, inhibiting AID expressed in epithelial malignancies could also have therapeutic value. Multiple mechanisms regulate AID to permit optimal antibody diversification while minimizing pathological side-effects [31, 32]. Controlling AID protein stability is an important regulatory instance [31]. We have shown that AID interacts with HSP90 and that treating human and mouse B cell lines with HSP90 inhibitors leads to ubiquitin-dependent proteasomal degradation of endogenous and transfected AID in the cytoplasm [33]. Since 90% of AID is cytoplasmic [34], inhibiting the HSP90 molecular chaperoning pathway causes a dose-responsive decrease in the cellular AID levels through protein destabilization, and reduces SHM and CSR in vitro [33, 35]. HSP90 inhibitors show promising clinical activity against various cancers [36, 37] and have gone through security, toxicity and bioavailability tests in animals and humans; providing a practical possibility for targeting AID in vivo. It is also important to determine whether they affect AID and the antibody response to better evaluate the outcome of those clinical trials. Here, we provide evidence that AID protein levels and activity can be reduced in vivo by the HSP90 inhibitor 17-DMAG, currently in clinical trials [38-41]. We additionally show that AID.