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Epigenetic suppression of SLFN11 in germinal center B-cells during B-cell development

Fumiya Moribe1, Momoko Nishikori1, Tsuyoshi Takashima2

  • 1Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Plos One
|January 29, 2021
PubMed
Abstract

Insights

Schlafen-11 (SLFN11) is epigenetically suppressed in normal germinal center B-cells (GCBs) and GCB-derived lymphomas. Combining epigenetic modifiers with cytosine arabinoside offers a potential treatment for GCB-derived lymphomas with low SLFN11 expression.

Area of Science:

  • Cell Biology
  • Cancer Biology
  • Immunology

Background:

  • Schlafen-11 (SLFN11) executes cancer cells under genotoxic stress but its role in physiological conditions is unclear.
  • Germinal center B-cells (GCBs) experience genotoxic stress during B-cell development, suggesting a potential role for SLFN11 regulation.

Purpose of the Study:

  • To investigate the expression profile of SLFN11 during normal B-cell development and in B-cell-derived cancers.
  • To determine the regulatory mechanisms of SLFN11 expression in GCBs.
  • To evaluate therapeutic strategies targeting SLFN11 in GCB-derived lymphomas.

Main Methods:

  • Analyzed SLFN11 mRNA and protein expression in normal B-cell stages and B-cell cancer cell lines.
  • Utilized dual immunohistochemical staining for SLFN11 in human lymphatic tissues.
  • Investigated the effect of epigenetic modifiers (EZH2 and HDAC inhibitors) on SLFN11 expression and drug sensitivity in GCB-derived lymphoma cells.

Main Results:

  • SLFN11 expression was low in normal GCBs and GCB-like diffuse large B-cell lymphoma (DLBCL).
  • Immunohistochemistry revealed low SLFN11 in GCBs, increasing in plasmablasts and plasmacytes.
  • Epigenetic modifiers (tazemetostat, panobinostat) upregulated SLFN11 in GCB-derived lymphoma cells, increasing sensitivity to cytosine arabinoside.

Conclusions:

  • SLFN11 expression is epigenetically suppressed in normal GCBs and GCB-derived lymphomas.
  • GCB-derived lymphomas with low SLFN11 expression are potential candidates for combination therapy with epigenetic modifiers and cytosine arabinoside.

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