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

被引：19

作者：

Moribe, Fumiya ^{[1
]}

Nishikori, Momoko ^{[1
]}

Takashima, Tsuyoshi ^{[2
]}

Taniyama, Daiki ^{[3
]}

Onishi, Nobuyuki ^{[4
]}

Arima, Hiroshi ^{[1
]}

Sasanuma, Hiroyuki ^{[5
]}

Akagawa, Remi ^{[5
]}

Elloumi, Fathi ^{[6
,7
]}

Takeda, Shunichi ^{[5
]}

Pommier, Yves ^{[6
,7
]}

Morii, Eiichi ^{[2
]}

Takaori-Kondo, Akifumi ^{[1
]}

Murai, Junko ^{[8
]}

机构：

[1] Kyoto Univ, Grad Sch Med, Dept Hematol & Oncol, Kyoto, Japan

[2] Osaka Univ, Grad Sch Med, Dept Pathol, Osaka, Japan

[3] Hiroshima Univ, Grad Sch Biomed & Hlth Sci, Dept Mol Pathol, Hiroshima, Japan

[4] Keio Univ, Sch Med, Inst Adv Med Res, Div Gene Regulat, Tokyo, Japan

[5] Kyoto Univ, Grad Sch Med, Dept Radiat Genet, Kyoto, Japan

[6] NCI, Dev Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[7] NCI, Lab Mol Pharmacol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[8] Keio Univ, Inst Adv Biosci, Tsuruoka, Yamagata, Japan

来源：

PLOS ONE | 2021年 / 16卷 / 01期

基金：

日本学术振兴会;

关键词：

PROTEIN-SYNTHESIS; EXPRESSION; LYMPHOMA; QUANTIFICATION; SENSITIVITY; ACTIVATION; BLIMP-1; GENES; PAX5; AID;

D O I：

10.1371/journal.pone.0237554

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：20

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