Ewing sarcoma 11;22 translocation produces a chimeric transcription factor that requires the DNA-binding domain encoded by FLI1 for transformation.
The 11;22 chromosomal translocation specifically linked to Ewing sarcoma and primitive neuroectodermal tumor results in a chimeric molecule fusing the amino-terminal-encoding portion of the EWS gene to the carboxyl-terminal DNA-binding domain encoded by the FLI1 gene. We have isolated a fourth EWS-FLI1 fusion cDNA that is structurally distinct from the three forms previously described. To determine the transforming activity of this gene, alternative forms of the EWS-FLI1 fusion were transduced into NIH 3T3 cells. Cells expressing either type 1 or type 4 fusion constructs formed foci in culture and colonies in soft agar, indicating that EWS-FLI1 is a transforming gene. EWS-FLI1 deletion mutants were created to map functionally the critical regions within the chimera. Deletion of either the EWS domain or the FLI1 corresponding to the DNA-binding domain totally abrogated the ability for EWS-FLI1 to transform 3T3 cells. These data indicate that the oncogenic effect of the 11;22 translocation is caused by the formation of a chimeric transcription factor. Formation of chimeric transcription factors has now been demonstrated to promote tumors of both neuroectodermal and hematopoietic origin, suggesting that this may be a common mechanism in human carcinogenesis.
Department of Pediatrics, Gwynne Hazen Cherry Memorial Laboratories, University of California, Los Angeles 90024.
W A
WA
May
M L
ML
Gishizky
S L
SL
Lessnick
L B
LB
Lunsford
B C
BC
Lewis
O
O
Delattre
J
J
Zucman
G
G
Thomas
C T
CT
Denny
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002880:Chromosomes, Human, Pair 11; D002892:Chromosomes, Human, Pair 22; D004268:DNA-Binding Proteins / Q000235:genetics*; D005622:Friend murine leukemia virus / Q000235:genetics; D015723:Gene Library; D006801:Humans; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics*; D015183:Restriction Mapping; D012512:Sarcoma, Ewing / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D014170:Transformation, Genetic; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D016662:Virus Integration
D004268:DNA-Binding Proteins; D009838:Oligodeoxyribonucleotides; D011994:Recombinant Proteins; D014157:Transcription Factors