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IR@PKUHSC  > 北京大学第三临床医学院  > 期刊论文
学科主题: 临床医学
题名:
Global Promoter Methylation Analysis Reveals Novel Candidate Tumor Suppressor Genes in Natural Killer Cell Lymphoma
作者: Kuecuek, Can1; Hu, Xiaozhou1,2; Jiang, Bei3; Klinkebiel, David4; Geng, Huimin5; Gong, Qiang1; Bouska, Alyssa3; Iqbal, Javeed3; Gaulard, Philippe6; McKeithan, Timothy W.1; Chan, Wing C.1
刊名: CLINICAL CANCER RESEARCH
发表日期: 2015-04-01
DOI: 10.1158/1078-0432.CCR-14-1216
卷: 21, 期:7, 页:1699-1711
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Oncology
研究领域[WOS]: Oncology
关键词[WOS]: ACUTE LYMPHOBLASTIC-LEUKEMIA ; PERIPHERAL T-CELL ; L-ASPARAGINASE ; DNA HYPERMETHYLATION ; CANCER ; MALIGNANCIES ; EXPRESSION ; SOCS6 ; STAT3 ; TET2
英文摘要:

Purpose: To Identify tumor suppressor genes epigenetically silenced by promoter hypermethylation in extranodal natural killer cell lymphoma (NKCL).

Experimental Design: Promoter methylation was analyzed with global and locus-specific methylation assays in NKCL cases and NK cell lines. Gene expression profiles were used to identify genes for which aberrant promoter methylation was associated with transcriptional silencing. Selected DNA methylations were validated by RRBS, pyrosequencing, or q-MSP. Decitabine treatment was performed to evaluate reactivation of methylated genes. The tumor suppressor effect of silenced genes was evaluated functionally by reintroducing them into NK cell lines.

Results: We observed significant promoter hypermethylation in most NKCL samples compared with normal NK cells. Correlation of global promoter methylation with gene expression profiles identified 95 genes with strong evidence for being silenced because of promoter methylation, including BCL2L11 (BIM), DAPK1, PTPN6 (SHP1), TET2, SOCS6, and ASNS. Known tumor suppressor genes were significantly overrepresented in this set of genes. Decitabine treatment of NK cell lines was associated with reexpression of all 10 selected methylated and silenced genes. Ectopic expression of frequently silenced BIM in two BIM-nonexpressing NK cell lines led to increased apoptosis and eventual elimination of BIM-transduced cells. It also sensitized these cell lines to chemotherapy-induced apoptosis. Similarly, reintroduction of SOCS6 significantly inhibited growth in SOCS6-nonexpressing NK cell lines. NK cell lines lacking ASNS expression showed increased sensitivity to treatment with l-asparaginase. Reintroduction of ASNS reduced drug sensitivity.

Conclusion: Promoter region hypermethylation is frequent in NKCL, and aberrantly methylated genes are pathologically and clinically significant. (C) 2015 AACR.

语种: 英语
所属项目编号: 1S10RR027754-01 ; 5P20RR016469 ; RR018788-08 ; 8P20GM103427 ; GM103471-09
项目资助者: NCRR ; National Institute for General Medical Science (NIGMS)
WOS记录号: WOS:000352076700024
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/50478
Appears in Collections:北京大学第三临床医学院_期刊论文

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作者单位: 1.City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA
2.Peking Univ, Hosp 3, Dept Clin Lab, Beijing 100871, Peoples R China
3.Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA
4.Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, Omaha, NE USA
5.Univ Calif San Francisco, Sch Med, Dept Lab Med, San Francisco, CA USA
6.Univ Paris Est, Inserm U955, Grp Henri Mondor Albert Cherlevier, Dept Pathol, Creteil, France

Recommended Citation:
Kuecuek, Can,Hu, Xiaozhou,Jiang, Bei,et al. Global Promoter Methylation Analysis Reveals Novel Candidate Tumor Suppressor Genes in Natural Killer Cell Lymphoma[J]. CLINICAL CANCER RESEARCH,2015,21(7):1699-1711.
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