BCR-ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients
BCR-ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients
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DOI：
10.1038/onc.2010.409
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发表时间：
2011-01-01
期刊：
影响因子：
8
通讯作者：
Amarante-Mendes, G. P.
中科院分区：
文献类型：
--
作者：
De Carvalho, D. D.;Binato, R.;Amarante-Mendes, G. P.
肿瘤坏死因子相关凋亡诱导配体-TNFSF 10（TRAIL）是TNF-α家族的一员，也是一种死亡受体配体，显示出选择性杀死肿瘤细胞。毫不奇怪，TRAIL在多种肿瘤细胞中下调，包括BCR-ABL阳性白血病。尽管我们对TRAIL介导的细胞杀伤的分子基础了解很多，但肿瘤中负责TRAIL抑制的机制仍然不清楚，因为（a）TRAIL可以由视黄酸（RA）调节;（B）显示黑素瘤的肿瘤抗原优先表达抗原（PRAME）通过多梳蛋白、zeste同源物增强子2（EZH 2）抑制RA受体靶基因的转录;（c）我们发现慢性粒细胞白血病（CML）患者中TRAIL与BCR-ABL呈负相关。因此，我们决定研究PRAME、EZH 2和TRAIL在BCR-ABL阳性白血病中的相关性。在这里，我们证明了PRAME，而不是EZH 2，在BCR-ABL细胞中上调，并与CML患者的疾病进展有关。在这些患者中，PRAME与BCR-ABL之间呈正相关，PRAME与TRAIL之间呈负相关。重要的是，在BCR-ABL阳性细胞系中通过RNA干扰敲低PRAME或EZH 2恢复TRAIL表达。此外，在CML细胞系中存在EZH 2结合在TRAIL的启动子区上的富集。这种结合在PRAME敲除后丢失。最后，敲低PRAME或EZH 2，并因此诱导TRAIL表达，增强伊马替尼敏感性。总之，我们的数据揭示了一种新的调节机制，负责降低TRAIL的表达，并提供了基础的替代目标，联合治疗策略的CML。Oncogene（2011）30，223-233; doi：10.1038/onc.2010.409; 2010年9月13日在线发表
Tumor necrosis factor-related apoptosis-inducing ligand-TNFSF10 (TRAIL), a member of the TNF-alpha family and a death receptor ligand, was shown to selectively kill tumor cells. Not surprisingly, TRAIL is downregulated in a variety of tumor cells, including BCR-ABL-positive leukemia. Although we know much about the molecular basis of TRAIL-mediated cell killing, the mechanism responsible for TRAIL inhibition in tumors remains elusive because (a) TRAIL can be regulated by retinoic acid (RA); (b) the tumor antigen preferentially expressed antigen of melanoma (PRAME) was shown to inhibit transcription of RA receptor target genes through the polycomb protein, enhancer of zeste homolog 2 (EZH2); and (c) we have found that TRAIL is inversely correlated with BCR-ABL in chronic myeloid leukemia (CML) patients. Thus, we decided to investigate the association of PRAME, EZH2 and TRAIL in BCR-ABL-positive leukemia. Here, we demonstrate that PRAME, but not EZH2, is upregulated in BCR-ABL cells and is associated with the progression of disease in CML patients. There is a positive correlation between PRAME and BCR-ABL and an inverse correlation between PRAME and TRAIL in these patients. Importantly, knocking down PRAME or EZH2 by RNA interference in a BCR-ABL-positive cell line restores TRAIL expression. Moreover, there is an enrichment of EZH2 binding on the promoter region of TRAIL in a CML cell line. This binding is lost after PRAME knockdown. Finally, knocking down PRAME or EZH2, and consequently induction of TRAIL expression, enhances Imatinib sensibility. Taken together, our data reveal a novel regulatory mechanism responsible for lowering TRAIL expression and provide the basis of alternative targets for combined therapeutic strategies for CML. Oncogene (2011) 30, 223-233; doi:10.1038/onc.2010.409; published online 13 September 2010