| Full text | |
| Author(s): Show less - |
De Carvalho, D. D.
[1, 2]
;
Binato, R.
[3]
;
Pereira, W. O.
[1, 2]
;
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.
[1, 7]
;
Jacysyn, J. F.
[8]
;
Amarante-Mendes, G. P.
[1, 2]
Total Authors: 13
|
| Affiliation: | [1] Inst Nacl Ciencia & Tecnol, Inst Invest Imunol, Sao Paulo - Brazil
[2] Univ Sao Paulo, Dept Immunol, Inst Ciencias Biomed, BR-05508900 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 |
| 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. (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 Opportunities: | Scholarships in Brazil - Doctorate (Direct) |