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

Authors: De Carvalho, DD  Binato, R  Pereira, WO  Leroy, JM  Colassanti, MD  Proto-Siqueira, R  Bueno-Da-Silva, AE  Zago, MA  Zanichelli, MA  Abdelhay, E  Castro, FA  Jacysyn, JF  Amarante-Mendes, GP 
Citation: De Carvalho DD, etal., Oncogene. 2011 Jan 13;30(2):223-33. doi: 10.1038/onc.2010.409. Epub 2010 Sep 13.
Pubmed: (View Article at PubMed) PMID:20838376
DOI: Full-text: DOI:10.1038/onc.2010.409

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.

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CRRD Object Information
CRRD ID: 11535035
Created: 2016-09-19
Species: All species
Last Modified: 2016-09-19
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.