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BCR–ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand—TNFSF10 (TRAIL), a member of the TNF-α 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.

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Acknowledgements

DDC, JMGL, WOP and AEBBS were recipients of fellowships from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP—Brazil). This work was supported by grants from FAPESP and from the Brazilian Research Council (CNPq—Brazil). We thank Drs Phillippa Taberlay, Jueng Soo You and Theresa Kelly for their critical review of the paper.

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Correspondence to G P Amarante-Mendes.

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De Carvalho, D., Binato, R., Pereira, W. et al. BCR–ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients. Oncogene 30, 223–233 (2011). https://doi.org/10.1038/onc.2010.409

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