title: 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.
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: D D
authors.initials: DD
authors.lastname: De Carvalho
authors.forename: R
authors.initials: R
authors.lastname: Binato
authors.forename: W O
authors.initials: WO
authors.lastname: Pereira
authors.forename: J M G
authors.initials: JM
authors.lastname: Leroy
authors.forename: M D
authors.initials: MD
authors.lastname: Colassanti
authors.forename: R
authors.initials: R
authors.lastname: Proto-Siqueira
authors.forename: A E B
authors.initials: AE
authors.lastname: Bueno-Da-Silva
authors.forename: M A
authors.initials: MA
authors.lastname: Zago
authors.forename: M A
authors.initials: MA
authors.lastname: Zanichelli
authors.forename: E
authors.initials: E
authors.lastname: Abdelhay
authors.forename: F A
authors.initials: FA
authors.lastname: Castro
authors.forename: J F
authors.initials: JF
authors.lastname: Jacysyn
authors.forename: G P
authors.initials: GP
authors.lastname: Amarante-Mendes
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000032:analysis / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein; D016044:Fusion Proteins, bcr-abl / Q000032:analysis / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use; D063151:Polycomb Repressive Complex 2; D011401:Promoter Regions, Genetic; D011743:Pyrimidines / Q000627:therapeutic use; D034622:RNA Interference; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000032:analysis / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D001549:Benzamides; D004268:DNA-Binding Proteins; C404944:PRAME protein, human; D010879:Piperazines; D011743:Pyrimidines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014157:Transcription Factors; D000068877:Imatinib Mesylate; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D016044:Fusion Proteins, bcr-abl