Global Promoter Methylation Analysis Reveals Novel Candidate Tumor Suppressor Genes in Natural Killer Cell Lymphoma

被引：81

作者：

Kuecuek, Can ^{[1
]}

Hu, Xiaozhou ^{[1
,2
]}

Jiang, Bei ^{[3
]}

Klinkebiel, David ^{[4
]}

Geng, Huimin ^{[5
]}

Gong, Qiang ^{[1
]}

Bouska, Alyssa ^{[3
]}

Iqbal, Javeed ^{[3
]}

Gaulard, Philippe ^{[6
]}

McKeithan, Timothy W. ^{[1
]}

Chan, Wing C. ^{[1
]}

机构：

[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

来源：

CLINICAL CANCER RESEARCH | 2015年 / 21卷 / 07期

关键词：

ACUTE LYMPHOBLASTIC-LEUKEMIA; PERIPHERAL T-CELL; L-ASPARAGINASE; DNA HYPERMETHYLATION; CANCER; MALIGNANCIES; EXPRESSION; SOCS6; STAT3; TET2;

D O I：

10.1158/1078-0432.CCR-14-1216

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

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.

引用

页码：1699 / 1711

页数：13

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