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bioRxiv · 10.1101/2020.07.30.228650

Epigenetic suppression of SLFN11 in germinal center B cells in the process of the dynamic expression change during B-cell development

Moribe, F.·Nishikori, M.·Sasanuma, H.·Akagawa, R.·Arima, H.·Takeda, S.·Takaori-Kondo, A.·Murai, J.
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Abstract

BackgroundSLFN11 enhances cellular toxicity of genotoxic anti-cancer agents, and its important role under physiological conditions has not been appreciated yet. Somatic hypermutations and class switch recombination that can cause physiological genotoxic stress arise in germinal center B cells (GCBs). GCBs are a major origin of B-cell lymphomas that are frequently treated by cytosine arabinoside, a genotoxic anti-cancer agent. ObjectiveTo clarify the expression profile of SLFN11 in different stages of B cells and B-cell lymphomas. MethodsWe analyzed the expression of SLFN11 by mining publicly available databases for different stages of normal B cells and various types of B-cell lymphoma lines and also by performing immunohistochemical staining of human lymph nodes. We investigated the effects of two epigenetic modifiers, an EZH2 inhibitor, tazemetostat (EPZ6438) and a histone deacetylase inhibitor, panobinostat (LBH589) on SLFN11 expression in B-cell lymphoma lines and examined the therapeutic efficacy of these epigenetic modifiers in the combination with cytosine arabinoside. ResultsSLFN11 expression was specifically low in GCBs compared to non-GCBs, which was consolidated by the immunohistochemical staining for SLFN11 with human lymph nodes. SLFN11 expression levels in B-cell lymphoma lines largely correlated to those of their normal counterparts. The epigenetic modifiers upregulated SLFN11 expression in GCB-derived lymphomas and made the lymphomas further susceptible to cytosine arabinoside. ConclusionsThe expression of SLFN11 may be epigenetically suppressed in GCBs and GCB-derived lymphomas. GCB-derived lymphomas with low SLFN11 expression can be treated by the combination of epigenetic modifiers and cytosine arabinoside.

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Moribe, F., Nishikori, M., Sasanuma, H., Akagawa, R., Arima, H., Takeda, S., Takaori-Kondo, A., Murai, J.. 2020-07-30. Epigenetic suppression of SLFN11 in germinal center B cells in the process of the dynamic expression change during B-cell development. https://doi.org/10.1101/2020.07.30.228650

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