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

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... Full description

Journal Title: Oncogene 2010, Vol.30(2), p.223
Main Author: D D De Carvalho
Other Authors: R Binato , W O Pereira , J M G Leroy , M D Colassanti , R Proto-Siqueira , A E B Bueno-Da-Silva , M A Zago , M A Zanichelli , E Abdelhay , F A Castro , J F Jacysyn , G P Amarante-Mendes
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ID: ISSN: 0950-9232 ; E-ISSN: 1476-5594 ; DOI: 10.1038/onc.2010.409
Link: http://dx.doi.org/10.1038/onc.2010.409
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recordid: nature_a10.1038/onc.2010.409
title: BCR–ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients
format: Article
creator:
  • D D De Carvalho
  • R Binato
  • W O Pereira
  • J M G Leroy
  • M D Colassanti
  • R Proto-Siqueira
  • A E B Bueno-Da-Silva
  • M A Zago
  • M A Zanichelli
  • E Abdelhay
  • F A Castro
  • J F Jacysyn
  • G P Amarante-Mendes
subjects:
  • Chronic Myeloid Leukemia -- Development And Progression
  • Chronic Myeloid Leukemia -- Research
  • Tumor Necrosis Factor -- Physiological Aspects
  • Tumor Necrosis Factor -- Research
  • Ligands (Biochemistry) -- Physiological Aspects
  • Ligands (Biochemistry) -- Research
ispartof: Oncogene, 2010, Vol.30(2), p.223
description: 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 Keywords: PRAME; TRAIL; TNFSF10; EZH2; CML; BCR-ABL
language:
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identifier: ISSN: 0950-9232 ; E-ISSN: 1476-5594 ; DOI: 10.1038/onc.2010.409
fulltext: fulltext
issn:
  • 0950-9232
  • 09509232
  • 1476-5594
  • 14765594
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titleBCR–ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients
creatorD D De Carvalho ; R Binato ; W O Pereira ; J M G Leroy ; M D Colassanti ; R Proto-Siqueira ; A E B Bueno-Da-Silva ; M A Zago ; M A Zanichelli ; E Abdelhay ; F A Castro ; J F Jacysyn ; G P Amarante-Mendes
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descriptionTumor 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 Keywords: PRAME; TRAIL; TNFSF10; EZH2; CML; BCR-ABL
subjectChronic Myeloid Leukemia -- Development And Progression ; Chronic Myeloid Leukemia -- Research ; Tumor Necrosis Factor -- Physiological Aspects ; Tumor Necrosis Factor -- Research ; Ligands (Biochemistry) -- Physiological Aspects ; Ligands (Biochemistry) -- Research;
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