In approximately 70% of human extraskeletal myxoid chondrosarcoma (EMC) tumors, a t(9;22) chromosome translocation gives rise to a fusion protein, named EWS/NOR1, containing the amino-terminal domain of EWS fused to the complete amino acid sequence of the nuclear receptor NOR1. Several observations suggest that one role of EWS/NOR1 in EMC may be to deregulate the expression of specific genes involved in the tumoral process. In order to identify these genes, we have used a CFK2 chondrogenic cell line over-expressing EWS/NOR1. A differential display analysis has identified the PLAGL1 gene as being down-regulated in the CFK2(EWS/NOR1) cell line compared to native CFK2 cells. RT-PCR analyses show that whereas the PLAGL1 mRNAs encoding the two isoforms of the protein are highly expressed in four human chondrocyte immortalized cell lines and two human chondrocyte primary cultures, they are strongly down-regulated in six EMC tumors. We conclude that down-regulation of PLAGL1 may be a significant contributing factor in the development of EMC tumors.