23532

PRAME

CT130|MAPE|OIP4;preferentially expressed antigen in melanoma;PRAME;preferentially expressed antigen in melanoma

OIP-4|Opa-interacting protein OIP4|cancer/testis antigen 130|melanoma antigen preferentially expressed in tumors|opa-interacting protein 4|preferentially expressed antigen of melanoma

22q11.22

protein-coding

The expression of the PRAME gene (preferentially expressed antigen of melanoma) was measured by quantitative reverse transcriptase polymerase chain reaction in 50 children with newly diagnosed acute myeloid leukemia (AML), three samples of CD34(+) stem cells, six bone marrow samples, and 10 peripheral blood samples of healthy donors, as well as three AML cell-lines (KG-1, U937, and HL-60). Eight patients were also analyzed in relapse. Contrary to previous reports, we could show that the PRAME gene is expressed by CD34(+) stem cells. This might constitute a problem in using PRAME for tumor immunotherapy. Overexpression of PRAME was found in 62% (n=31) of our patients. The rates of overall and disease-free survival in this group were higher than in patients with no or low expression (P<0.05). PRAME expression was negatively correlated to the white blood cell count at diagnosis (P<0.05) and significantly higher in patients witht(8;21). The levels of expression at diagnosis corresponded with those at relapse (P<0.001) and increased levels could be found prior to the relapse in one patient who was regularly monitored. Our results suggest that the expression of PRAME isan indicator of favorable prognosis and could be a useful tool for monitoring minimal residual disease in childhood AML.

The gene PRAME (preferentially expressed antigen of melanoma) was found to be expressed at high levels in a large fraction of different tumors and adult leukemias. Since PRAME is only expressed at low levels in a few normal tissues and encodes an antigen recognized by autologous cytolytic T lymphocytes, it might be a good candidate for tumor immunotherapy. In this study, quantitative reversetranscriptase polymerase chain reaction was used to measure PRAME gene expression in 50 children with newly diagnosed acute lymphoblastic leukemia (ALL). Nine patients were also analyzed in relapse. Overexpression of PRAME was found in 42%(N = 21) of the patients. In accordance with our findings in acute myeloblastic leukemia (AML) patients, the rate of disease-free survival was higher and white blood cell counts at diagnosis were lower in patients with an overexpression of PRAME. However, in our group of ALL patients these findings were not statistically significant. The levels of expression at diagnosis corresponded well with those at relapse (P = 0.017). Although overexpression of PRAME was less frequent than in children with AML (62%) our results suggest that PRAME could bea useful target for immunotherapy in some children with ALL.

Preferentially expressed antigen of melanoma (PRAME) is expressed in a wide variety of tumors, but in contrast with most other tumor associated antigens, itis also expressed in leukemias. In a previous study, we showed that overexpression of PRAME induced apoptosis, inhibited cell proliferation and reduced tumorigenicity of leukemic cells in vivo. We also demonstrated that PRAME overexpression induced the repression of three genes (Hsp27, S100A4 and p21) associated with an unfavorable prognosis in leukemia. Here, we further investigated the mechanisms of PRAME-induced tumor suppression in vitro and in vivo. We performed a gene profiling study by analysing PRAME shRNA-silenced leukemic cells on high-density micro-arrays (Affymetrix) and found that PRAME altered the expression of two additional genes potentially involved in cancerogenesis and cancer progression: IL-8 and IGFBP-2. In a series of 28 acutemyeloid leukemia pediatric patients, we observed that PRAME expression was associated with an increased leukemia-free survival. Importantly, the correlation between PRAME expression in leukemic cell lines and the decreased expression of Hsp27, S100A4, p21, IL-8 and the increased expression of IGFBP-2 was also observed in vivo, in leukemic patients. Our results suggest that the favorable prognosis of PRAME could be mediated, at least in part, by the modified expression of those genes.

Medulloblastoma is the most common malignant tumors of central nervous system inthe childhood. The treatment is severe, harmful and, thus, has a dismal prognosis. As PRAME is present in various cancers, including meduloblastoma, andhas limited expression in normal tissues, this antigen can be an ideal vaccine target for tumor immunotherapy. In order to find a potential molecular target, we investigated PRAME expression in medulloblastoma fragments and we compare the results with the clinical features of each patient. Analysis of gene expression was performed by real-time quantitative PCR from 37 tumor samples. The Mann-Whitney test was used to analysis the relationship between gene expression and clinical characteristics. Kaplan-Meier curves were used to evaluate survival. PRAME was overexpressed in 84% samples. But no statistical association was foundbetween clinical features and PRAME overexpression. Despite that PRAME gene could be a strong candidate for immunotherapy since it is highly expressed in medulloblastomas.