INDUCTION OF APOPTOSIS IN RHABDOMYOSARCOMA CELLS THROUGH DOWN-REGULATION OF PAX PROTEINS

The expression of a number of human paired box-containing (PAX) genes has been correlated with various types of tumors, Novel fusion genes e ncoding chimeric fusion proteins have been found in the pediatric mali gnant tumor alveolar rhabdomyosarcoma (RMS). They are generated by two chromosomal translocations t(2;13) and t(1;13) juxtaposing PAX3 or PA X7, respectively, with a forkhead domain gene FKHR. Here we describe t hat specific down-regulation of the t(2;13) translocation product in a lveolar RMS cells by antisense oligonucleotides results in reduced cel lular viability, Cells of embryonal RMS, the other major histiotype of this tumor, were found to express either wild type PAX3 or PAX7 at el evated levels when compared with primary human myoblasts, Treatment of corresponding embryonal RMS cells with antisense olignucleotides dire cted against the mRNA translational start site of either one of these two transcription factors similarly triggers cell death, which is most likely due to induction of apoptosis, Retroviral mediated ectopic exp ression of mouse Pax3 in a PAX7 expressing embryonal RMS cell line cou ld partially rescue antisense induced apoptosis. These data suggest th at the PAX3/FKHR fusion gene and wild-type PAX genes play a causative role in the formation of RMS and presumably other tumor types, possibl y by suppressing the apoptotic program that would normally eliminate t hese cells.