Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses
Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses
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DOI：
10.1182/blood-2011-04-346890
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发表时间：
2011-09-22
期刊：
影响因子：
20.3
通讯作者：
Seto, Masao
中科院分区：
文献类型：
--
作者：
Karube, Kennosuke;Nakagawa, Masao;Seto, Masao
寡核苷酸阵列比较基因组杂交（CGH）和基因表达谱的自然杀伤（NK）细胞肿瘤，在努力描绘的分子发病机制。Oligoarray CGH确定了两个最常缺失的6 q21区域（39个中的14个或36%）。其中一个区域包括POPDC 3、PREP、PRDM 1、ATG 5和AIM 1，而另一个区域包括LACE 1和FOXO 3。位于这些区域的所有基因，除了POPDC 3和AIM 1，在肿瘤样品中下调，通过基因表达分析确定，因此被认为是候选肿瘤抑制基因。位于6 q21 -23上的已知肿瘤抑制基因A20和HACE 1被列为候选基因，因为它们也表现出频繁的基因组缺失和表达下调。随后建立Tet-Off NK细胞系NKL用于功能分析。将7个候选基因转导到Tet-Off NKL中，并诱导强制再表达。FOXO 3和PRDM 1的再表达抑制NKL增殖，但其他基因的再表达后情况并非如此。使用另一种NK细胞系SNK 10证实了这种效果。此外，基因组分析检测到PRDM 1的无义突变，导致一个细胞系和一个临床样品中的功能失活。PRDM 1和FOXO 3被认为在NK细胞肿瘤的发病机制中起重要作用。（血。2011;118（12）：3195-3204）
Oligo-array comparative genomic hybridization (CGH) and gene-expression profiling of natural killer (NK)-cell neoplasms were used in an effort to delineate the molecular pathogenesis involved. Oligoarray CGH identified two 6q21 regions that were most frequently deleted (14 of 39 or 36%). One of these regions included POPDC3, PREP, PRDM1, ATG5, and AIM1, whereas the other included LACE1 and FOXO3. All genes located in these regions, except for POPDC3 and AIM1, were down-regulated in neoplastic samples, as determined by gene-expression analysis, and were therefore considered to be candidate tumor-suppressor genes. A20 and HACE1, the well-known tumor-suppressor genes located on 6q21-23, were included as candidate genes because they also demonstrated frequent genomic deletions and down-regulated expression. The Tet-Off NK cell line NKL was subsequently established for functional analyses. Seven candidate genes were transduced into Tet-Off NKL and forced re-expression was induced. Re-expression of FOXO3 and PRDM1 suppressed NKL proliferation, but this was not the case after re-expression of the other genes. This effect was confirmed using another NK cell line, SNK10. Furthermore, genomic analyses detected nonsense mutations of PRDM1 that led to functional inactivation in one cell line and one clinical sample. PRDM1 and FOXO3 are considered to play an important role in the pathogenesis of NK-cell neoplasms. (Blood. 2011;118(12):3195-3204)