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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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De Carvalho, D. D. [1, 2] ; Binato, R. [3] ; Pereira, W. O. [2, 1] ; Leroy, J. M. G. [1, 2] ; Colassanti, M. D. [4] ; Proto-Siqueira, R. [5] ; Bueno-Da-Silva, A. E. B. [1, 2] ; Zago, M. A. [6] ; Zanichelli, M. A. [4] ; Abdelhay, E. [3] ; Castro, F. A. [2, 7] ; Jacysyn, J. F. [8] ; Amarante-Mendes, G. P. [1, 2]
Total Authors: 13
[1] Univ Sao Paulo, Dept Immunol, Inst Ciencias Biomed, BR-05508900 Sao Paulo - Brazil
[2] Inst Nacl Ciencia & Tecnol, Inst Invest Imunol, Sao Paulo - Brazil
[3] Inst Nacl Canc, Div Labs CEMO, Rio De Janeiro - Brazil
[4] Hosp Brigadeiro, Sao Paulo - Brazil
[5] Fleury Med & Hlth, Sao Paulo - Brazil
[6] Univ Sao Paulo, Fac Med Ribeirao Preto, BR-05508900 Sao Paulo - Brazil
[7] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, BR-05508900 Sao Paulo - Brazil
[8] Univ Sao Paulo, Fac Med LIM62, BR-05508900 Sao Paulo - Brazil
Total Affiliations: 8
Document type: Journal article
Source: Oncogene; v. 30, n. 2, p. 223-233, Jan. 2011.
Field of knowledge: Biological Sciences - Immunology
Web of Science Citations: 30

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. (AU)

FAPESP's process: 05/58764-0 - BCR-ABL-mediated regulation of SH3BGRL2, D53, PRAME, DAP12 and calcineurin A beta and biological consequences of this regulation on CML
Grantee:Daniel Diniz de Carvalho
Support type: Scholarships in Brazil - Doctorate (Direct)