TLS FUS FUSION DOMAIN OF TLS FUS-ERG CHIMERIC PROTEIN RESULTING FROM THE T(1621) CHROMOSOMAL TRANSLOCATION IN HUMAN MYELOID-LEUKEMIA FUNCTIONS AS A TRANSCRIPTIONAL ACTIVATION DOMAIN

EWS and TLS/FUS genes, which code for RNA binding proteins are involve d in a wide variety of human solid tumors. The TLS/FUS gene is involve d both in human myxoid liposarcomas which carry a characteristic chrom osomal translocation, t(12;16)(q13;p11) and in human myeloid leukemias with recurrent chromosomal translocation, t(16;21)(p11:q22). The TLS/ FUS gene is fused to a transcriptional repressor, CHOP (in human myxoi d liposarcomas) or transcriptional activator, erg (in human myeloid le ukemias). To understand better the functional role of TLS/FUS-erg in h uman myeloid leukemias, we have cloned the TLS/FUS and TLS/FUS-erg cDN As and studied the functional properties of their gene products. TLS/F US protein binds to RNA in vitro and shows preferential binding to pol y G. Both the amino- and the carboxy- terminal regions of TLS/FUS cont aining the conserved RNA binding motifs are needed for poly G specific RNA binding activity. The TLS/FUS fusion domain (TFD) appears to regu late the DNA binding activity of TLS/FUS-erg chimeric protein which sh ows weaker transcriptional activation properties compared to normal er g proteins. Mutational analysis of the TLS/FUS-erg chimeric protein re veals TFD to function as a transcriptional activation domain thus repl acing the amino terminal transcriptional activation domain of the erg protein. Therefore alterations in both DNA binding and transcriptional activation properties of aberrant erg proteins may be responsible for the genesis of t(16;21) chromosomal translocation-bearing human myelo id leukemias.