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

Abstract

<strong>Background</strong> SLFN11 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. <strong>Objective</strong> To clarify the expression profile of <em>SLFN11</em> in different stages of B cells and B-cell lymphomas. <strong>Methods</strong> We analyzed the expression of <em>SLFN11</em> 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 <em>SLFN11</em> expression in B-cell lymphoma lines and examined the therapeutic efficacy of these epigenetic modifiers in the combination with cytosine arabinoside. <strong>Results</strong> <em>SLFN11 </em>expression was specifically low in GCBs compared to non-GCBs, which was consolidated by the immunohistochemical staining for SLFN11 with human lymph nodes. <em>SLFN11</em> expression levels in B-cell lymphoma lines largely correlated to those of their normal counterparts. The epigenetic modifiers upregulated <em>SLFN11</em> expression in GCB-derived lymphomas and made the lymphomas further susceptible to cytosine arabinoside. <strong>Conclusions</strong> The expression of <em>SLFN11</em> may be epigenetically suppressed in GCBs and GCB-derived lymphomas. GCB-derived lymphomas with low <em>SLFN11</em> expression can be treated by the combination of epigenetic modifiers and cytosine arabinoside.

Successful Treatment of Acute Uric Acid Nephropathy with Rasburicase in a Primary Central Nervous System Lymphoma Patient Showing Dramatic Response to Methotrexate – Case Report

“…The present case had a relatively high expression of SLFN11 by immunohistochemistry, suggesting sensitivity to chemotherapy (Figure 2C). Interestingly, a recent report suggests that non-germinal center B (non-GCB)-type lymphomas, the predominant type in PCNSL, have higher SLFN11 compared to GCB-type [11], although SLFN11 expression in PCNSL has not been studied to date. We analyzed the CellMinerCDB database and found that there was a weak, positive correlation between SLFN11 expression and sensitivity to methotrexate in lymphoma cell lines (r = 0.44, Supplemental figure 1) [12].…”

Successful Treatment of Acute Uric Acid Nephropathy with Rasburicase in a Primary Central Nervous System Lymphoma Patient Showing a Dramatic Response to Methotrexate—Case Report

“…The present case showed a relatively high expression of SLFN11 by immunohistochemistry, suggesting sensitivity to chemotherapy ( Figure 2 C). Interestingly, a recent report suggested that nongerminal center B (non-GCB)-type lymphomas, the predominant type in PCNSLs, have higher SLFN11 levels than the GCB-type ones [ 15 ], although the SLFN11 expression in PCNSLs has not been studied to date. We analyzed the CellMinerCDB database and found a weak positive correlation between the SLFN11 expression and the sensitivity to methotrexate in lymphoma cell lines (r = 0.44, Supplemental Figure S1 ) [ 16 ].…”

SLFN11 Inactivation Induces Proteotoxic Stress and Sensitizes Cancer Cells to Ubiquitin Activating Enzyme Inhibitor TAK-243

“…At the molecular level, SLFN11 targets DNA replication by binding to replication forks via replication protein A1 (RPA1) (2,3), blocking the replicative helicase complex (3), inducing the degradation of the replication initiation factor CDT1 (4) and stalled replication forks (5) and causing chromatin opening with activation of the stress response and immediate early response genes (IEGs) (6). Because approximately 50% of cancer cell lines and a large fraction of patient tumors do not express SLFN11 and are resistant to DNA replication-targeted therapies (1,(7)(8)(9)(10)(11)(12)(13)(14)(15), an unanswered question is how to target SLFN11-negative cancer cells.…”