AIDing cancer treatment: Reducing AID activity via HSP90 inhibition

Abstract

The activation induced deaminase (AID) catalyses the two key events underlying humoral adaptive immunity: class switch recombination and somatic hypermutation of antibody genes in B lymphocytes. AID accomplishes this task by directly deaminating cytosines within the genomic immunoglobulin locus, thereby triggering a complex mutagenic process eventually leading to improved effector function of antibodies. However, it has long been noticed that AID can be aberrantly expressed in cancer and that its activity is not absolutely restricted to antibody genes, as substantial genome-wide off-target mutations have been observed, which contribute to tumorigenesis and clonal evolution of AID-expressing malignancies. In this issue of the European Journal of Immunology, Montamat-Sicotte et al. [Eur. J. Immunol. 2015. 45: 2365–2376] investigate the feasibility and efficacy of in vivo inhibition of AID with HSP90 inhibitors in a mouse model of B-cell leukemia and in vitro with a human breast cancer cell line, thereby demonstrating that cancer patients may benefit from preventing noncanonical AID functions.

Immune signatures correlate with L1 retrotransposition in gastrointestinal cancers

“…as TLR and IFN signaling, to suppress L1s, in turn leading to hypermutation and increased RNA editing (Blanc and Davidson 2010;Roberts et al 2013;Rebhandl and Geisberger 2015;Orecchini et al 2017), and ultimately increasing the risk of impairing immune genes.…”

Epigenomic Modifications Mediating Antibody Maturation

“…The above observations suggest a possibility of using 17-AAG in the treatment of hypomethylated lymphomas (Figure 1 ). In a recent study 17-DMAG, a derivative of 17-AAG, has been found to reduce CSR and SHM in mice, while B-cell survival and proliferation remain unaffected ( 172 ).…”

Investigating epigenetic effects of activation-induced deaminase in chronic lymphocytic leukemia

“…Aside of these on-target activities, AID was also shown to perform substantial off-target effects by mediating genome wide mutations (off-target hypermutation) and translocations (off-target CSR) [3]. These off-target effects significantly contribute to lymphomagenesis as well as to clonal evolution and treatment resistance [4, 5]. Apart from these well described mutagenic effects, AID was also shown to contribute to DNA demethylation by deaminating methylated cytosines, thereby generating thymines, which are eventually replaced by unmethylated dCs by the DNA mismatch repair machinery independent of proliferation or DNA replication [6].…”