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PRAME is expressed in a wide variety of tumors, but in contrast with most other tumor associated antigens, it is also expressed in leukaemia. The physiological role of PRAME remains elusive. Interestingly, a high expression of PRAME seems to be predominantly found in acute leukemias subtypes carrying a favourable prognosis. Upon this clinical observation, we suspected that PRAME could improve the prognosis of acute leukemias by regulating cell death or cell cycle. To support this assumption, we investigated PRAME expression in a series of 26 pediatrics AML and we demonstrated that PRAME expression is correlated with a favorable prognosis. This correlation could be due either to an anti-PRAME immune response or a direct anti-tumorigenic effect of PRAME or both. To evaluate the importance of a direct effect of PRAME on cell death and cell cycle, we studied the effect of PRAME protein in cultured cell lines. We demonstrated that transient overexpression of PRAME induced a caspase-independent cell death in cultured cell lines (CHO-K1 and HeLa). Cells stably transfected with PRAME also exhibited a decreased proliferation rate due, at least partially, to an elevated basal rate of cell death. Immunocytochemistry of a FLAG-tagged PRAME, in vivo imaging of an EGFP-tagged PRAME and Western blotting after cell fractionation revealed a nuclear localization of the protein. Using a micro-array based approach, we showed that KG-1 leukemic cells stably transfected with PRAME presented a significant decrease of expression of the heat-shock protein Hsp27, the cyclin dependent kinase inhibitor p21 and the calcium-binding protein S100A4. The expression of these three proteins is known to inhibit apoptosis and has been associated with an unfavourable prognosis in a series of cancers. Finally, repression of PRAME expression by a siRNA strategy increased tumorigenicity of K562 leukemic cells in nude mice. {/MAIN;590;0;0;0;590;0;0}We suggest that all these observations might explain the favorable prognosis of the leukemias expressing high levels of PRAME. Obviously, these data do not exclude a possible role of immunity in the prognosis of PRAME-positive leukemias.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]