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

Abstract

BACKGROUND:

SLFN11 has recently been reported to execute cancer cells harboring replicative stress induced by DNA damaging agents. However, the roles of SLFN11 under physiological conditions remain poorly understood. Germinal center B-cells (GCBs) undergo somatic hypermutations and class-switch recombination, which can cause physiological genotoxic stress. Hence, we tested whether SLFN11 expression needs to be suppressed in GCBs during B-cell development.

OBJECTIVE:

To clarify the expression profile of SLFN11 in different developmental stages of B-cells and B-cell-derived cancers.

METHODS:

We analyzed the expression of SLFN11 by mining cell line databases for different stages of normal B-cells and various types of B-cell-derived cancer cell lines. We performed dual immunohistochemical staining for SLFN11 and B-cell specific markers in normal human lymphatic tissues. We tested the effects of two epigenetic modifiers, an EZH2 inhibitor, tazemetostat (EPZ6438) and a histone deacetylase inhibitor, panobinostat (LBH589) on SLFN11 expression in GCB-derived lymphoma cell lines. We also examined the therapeutic efficacy of these drugs in combination with cytosine arabinoside and the effects of SLFN11 on the efficacy of cytosine arabinoside in SLFN11-overexpressing cells.

RESULTS:

SLFN11 mRNA level was found low in both normal GCBs and GCB-DLBCL (GCB like-diffuse large B-cell lymphoma). Immunohistochemical staining showed low SLFN11 expression in GCBs and high SLFN11 expression in plasmablasts and plasmacytes. The EZH2 and HDAC epigenetic modifiers upregulated SLFN11 expression in GCB-derived lymphoma cells and made them more susceptible to cytosine arabinoside. SLFN11 overexpression further sensitized GCB-derived lymphoma cells to cytosine arabinoside.

CONCLUSIONS:

The expression of SLFN11 is epigenetically suppressed in normal GCBs and GCB-derived lymphomas. GCB-derived lymphomas with low SLFN11 expression can be treated by the combination of epigenetic modifiers and cytosine arabinoside.

• Authors: Fumiya Moribe, Momoko Nishikori, Tsuyoshi Takashima, Daiki Taniyama, Nobuyuki Onishi, Hiroshi Arima, Hiroyuki Sasanuma, Remi Akagawa, Fathi Elloumi, Shunichi Takeda, Yves Pommier, Eiichi Morii, Akifumi Takaori-Kondo, Junko Murai
• Journal: PloS one (PLoS One) Vol. 16 Issue 1 Pg. e0237554 ( 2021) ISSN: 1932-6203 [Electronic] United States
• PMID: 33513156 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Histone Deacetylase Inhibitors
• Nuclear Proteins
• Proto-Oncogene Proteins c-bcl-6
• SLFN11 protein, human

Topics

• B-Lymphocytes (immunology)
• Cell Line, Tumor
• Databases, Genetic
• Epigenesis, Genetic (drug effects)
• Epigenomics
• Gene Expression (genetics)
• Gene Expression Regulation, Neoplastic (genetics)
• Germinal Center (immunology)
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Lymphocyte Activation (drug effects)
• Lymphocytes (immunology)
• Lymphoma, Large B-Cell, Diffuse (pathology)
• Nuclear Proteins (genetics, metabolism)
• Plasma Cells (immunology)
• Proto-Oncogene Proteins c-bcl-6 (genetics)