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- Title
BCR-ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients.
- Authors
De Carvalho, D D; Binato, R; Pereira, W O; Leroy, J M G; Colassanti, M D; Proto-Siqueira, R; Bueno-Da-Silva, A E B; Zago, M A; Zanichelli, M A; Abdelhay, E; Castro, F A; Jacysyn, J F; Amarante-Mendes, G P
- 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.
- Subjects
CHRONIC myeloid leukemia; TUMOR necrosis factors; APOPTOSIS; CANCER cells; TRETINOIN; TUMOR antigens; IMATINIB
- Publication
Oncogene, 2011, Vol 30, Issue 2, p223
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2010.409