PRDM1 is a tumor suppressor gene in natural killer cell malignancies
PRDM1 is a tumor suppressor gene in natural killer cell malignancies
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DOI：
10.1073/pnas.1115128108
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发表时间：
2011-12-13
影响因子：
11.1
通讯作者：
Chan, Wing C.
中科院分区：
文献类型：
--
作者：
Kuecuek, Can;Iqbal, Javeed;Chan, Wing C.
自然杀伤细胞淋巴瘤（NKCL）是一种罕见的侵袭性非霍奇金淋巴瘤，其发病机制尚不清楚。在这里，我们表明，PRDM 1是一个肿瘤抑制基因在NKCL是失活的单等位基因缺失和启动子CpG岛超甲基化的组合。我们在18例NKCL中观察到8例（44%）PRDM 1基因座的单等位基因缺失。另一个等位基因在17例中的12例（71%）中显示出显著的启动子甲基化。为了支持其作为肿瘤抑制基因的作用，PRDM 1在PRDM 1缺失NK细胞系中的重建导致G2/M细胞周期停滞、细胞凋亡增加和强烈的负选择压力，伴随着表达PRDM 1的细胞的逐渐消除，当IL-2浓度受限时，这种负选择压力增强。我们观察到PRDM 1表达的逐步增加-特别是PRDM 1 α-在正常NK细胞中对IL-2的应答，以及在用工程化NK细胞靶K562-Cl 9-mb 21激活的正常NK细胞中，表明其在NK细胞稳态中的作用。为了支持这一作用，在正常NK细胞中通过shRNA敲低PRDM 1导致这些细胞的阳性选择。我们确定MYC和4-1BBL是NK细胞中PRDM 1的靶点。PRDM 1对内环境稳定控制的破坏可能是NKCL的重要发病机制。
Natural killer cell lymphoma (NKCL) constitutes a rare and aggressive form of non-Hodgkin lymphoma, and there is little insight into its pathogenesis. Here we show that PRDM1 is a tumor suppressor gene in NKCLs that is inactivated by a combination of monoallelic deletion and promoter CpG island hypermethylation. We observed monoallelic deletion of PRDM1 loci in 8 of 18 (44%) NKCL cases. The other allele showed significant promoter methylation in 12 of 17 (71%) cases. In support of its role as a tumor suppressor gene, the reconstitution of PRDM1 in PRDM1-null NK cell lines led to G2/M cell cycle arrest, increased apoptosis, and a strong negative selection pressure with progressive elimination of PRDM1-expressing cells, which was enhanced when IL-2 concentration is limiting. We observed a progressive increase in PRDM1 expression-in particular, PRDM1 alpha-in normal NK cells in response to IL-2 and in normal NK cells activated with an engineered NK cell target, K562-Cl9-mb21, suggesting its role in NK cell homeostasis. In support of this role, knockdown of PRDM1 by shRNA in normal NK cells resulted in the positive selection of these cells. We identified MYC and 4-1BBL as targets of PRDM1 in NK cells. Disruption of homeostatic control by PRDM1 may be an important pathogenetic mechanism for NKCL.