EWS/FLI1 is an oncogenic protein that is pathognomonic for Ewing sarcoma. [1] It is found in approximately 90% of all Ewing sarcoma tumors with the remaining 10% of fusions substituting one fusion partner with a closely related family member (e.g. ERG for FLI1). [2]
EWSR1 is a gene on chromosome 22 whose mRNA is translated into the protein Ewing sarcoma breakpoint region 1 (abbreviated EWS). The gene FLI1 resides on chromosome 11 where it encodes a member of the ETS transcription factor family, Friend leukemia integration 1 transcription factor (abbreviated FLI1).
Most fusions between EWS and FLI1 result from a t(11;22)(q24;q12) reciprocal chromosome translocation. [3] This translocation creates a chimeric transcript which fuses exons 1-7 of EWSR1 to exons 6-9 (or less commonly 5-9) of FLI1. [4] [5]
It has recently been appreciated that almost half of EWS and FLI1 fusions are a result of chromoplexy. [6] Evidence of chromoplectic looping is enriched in both metastatic and p53 mutant tumors. Chromoplectic looping appears to be the mechanism involved in forming the EWS/ERG variant transcription factor. This preference is probably due to EWSR1 and ERG being in opposite orientations on the genome precluding the production of functional EWS/ERG via a reciprocal translocation.
EWS/FLI1 functions as both a pioneering transcription factor and potent oncogene. [7] Its expression leads to a complete restructuring of the transcriptome of the cell of origin to favor a tumorigenic state. EWS/FLI1 accomplishes this through a set of complementary mechanisms:
EWS/FLI1 is an oncogenic protein that is pathognomonic for Ewing sarcoma. [1] It is found in approximately 90% of all Ewing sarcoma tumors with the remaining 10% of fusions substituting one fusion partner with a closely related family member (e.g. ERG for FLI1). [2]
EWSR1 is a gene on chromosome 22 whose mRNA is translated into the protein Ewing sarcoma breakpoint region 1 (abbreviated EWS). The gene FLI1 resides on chromosome 11 where it encodes a member of the ETS transcription factor family, Friend leukemia integration 1 transcription factor (abbreviated FLI1).
Most fusions between EWS and FLI1 result from a t(11;22)(q24;q12) reciprocal chromosome translocation. [3] This translocation creates a chimeric transcript which fuses exons 1-7 of EWSR1 to exons 6-9 (or less commonly 5-9) of FLI1. [4] [5]
It has recently been appreciated that almost half of EWS and FLI1 fusions are a result of chromoplexy. [6] Evidence of chromoplectic looping is enriched in both metastatic and p53 mutant tumors. Chromoplectic looping appears to be the mechanism involved in forming the EWS/ERG variant transcription factor. This preference is probably due to EWSR1 and ERG being in opposite orientations on the genome precluding the production of functional EWS/ERG via a reciprocal translocation.
EWS/FLI1 functions as both a pioneering transcription factor and potent oncogene. [7] Its expression leads to a complete restructuring of the transcriptome of the cell of origin to favor a tumorigenic state. EWS/FLI1 accomplishes this through a set of complementary mechanisms: