Epigenetic suppression of SLFN11 in germinal center B-cells during B-cell development.
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
Plasma Cells
/ immunology
Proto-Oncogene Proteins c-bcl-6
/ genetics
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2021
2021
Historique:
received:
25
07
2020
accepted:
07
12
2020
entrez:
29
1
2021
pubmed:
30
1
2021
medline:
1
5
2021
Statut:
epublish
Résumé
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. To clarify the expression profile of SLFN11 in different developmental stages of B-cells and B-cell-derived cancers. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 33513156
doi: 10.1371/journal.pone.0237554
pii: PONE-D-20-23146
pmc: PMC7846023
doi:
Substances chimiques
Histone Deacetylase Inhibitors
0
Nuclear Proteins
0
Proto-Oncogene Proteins c-bcl-6
0
SLFN11 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0237554Subventions
Organisme : Intramural NIH HHS
ID : Z01 BC006150
Pays : United States
Déclaration de conflit d'intérêts
We have read the journal's policy and the authors of this manuscript have the following competing interests: M.N. and A.T-K received honorarium and research funding from Eisai Co., Ltd. Other authors declare no conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
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