Complex downstream effects of nuclear export inhibition in B-cell lymphomas: a possible role for activation-induced cytidine deaminase (AID).

We read with great interest the recent paper by Azmi et al. who reported the in vitro and in vivo anti-lymphoma activity of novel specific inhibitors of nuclear export (SINE). The authors focused on targeting a main nuclear export protein called chromosome maintenance region 1 (CRM1) or exportin-1 (XPO1) because it had been reported to be a major player in drug resistance in many tumor types in which it might be over-expressed. A major obstacle for targeting XPO1 is the fact that it is responsible for the nuclear export of many proteins harboring canonical or non-canonical nuclear export signals. In their study, however, Azmi et al. claimed their new agent KPT-185 and its derivatives act highly specifically through covalent binding to the Cys-528 residue of XPO1. The authors also provided strong evidence that the observed activity was due to the blocking of the XPO1-mediated nuclear export of p53 and p73, which allowed their nuclear accumulation resulting in tumor suppression. We, however, would like to propose an additional mechanistic explanation for the observed pro-apoptotic effect when CRM1 is targeted in B-cell lymphomas. We propose that CRM1 inhibition in B-cell lymphomas affects the subcellular distribution of activation-induced cytidine deaminase (AID). AID is an essential enzyme for secondary immunoglobulin gene diversification through class switch recombination and somatic hypermutation by triggering DNA breaks. It is well-known that AID shuttles between the nucleus and cytoplasm to perform its functions, which is proposed to be one of the mechanisms for the tight regulation of its DNA damaging activity. Furthermore, AID has a well-defined nuclear export signal (NES) located at its C-terminus and shuttles in a CRM1dependent manner. Although AID mistargeting can cause oncogenic DNA lesions, which could lead to lymphomas, several studies suggested that increased levels of AID expression can trigger apoptotic cell death because of the higher levels of genotoxic stress. We have also shown previously that the increased resident time of AID in the nucleus can cause cell death in a Burkitt’s lymphoma cell