PgmNr Z6166: Ewsa inhibits TP53-mutation dependent tumorigenesis in zebrafish.

Authors:
Justin Mehojah 1 ; Richard Galbraith 2 ; Hyewon Park 1 ; Mizuki Azuma 1


Institutes
1) University of Kansas, Lawrence, KS; 2) Lawrence Memorial Hospital, Lawrence, KS.


Abstract:

ABSTRACT

Ewing sarcoma is a pediatric cancer of bone and soft tissue.  The common molecular abnormality identified in this disease is a chromosomal translocation, which results in the expression of a chimeric fusion protein containing EWS (Ewing sarcoma breakpoint region 1)-derived sequences in the amino terminus fused to the carboxyl-terminus of an ETS transcription factor (FLI1, ERG, ETV1, ETV4, or FEV).  Despite that the loss of EWS allele is a common character observed in this sarcoma, whether it contributes to the pathogenesis of Ewing sarcomas is unknown.  To address this question, we utilized a zebrafish mutant for ewsa (a homologue of human EWS).  Both ewsa/wt, Zygotic ewsa/ewsa and Maternal-Zygotic (MZ) ewsa/ewsa did not develop tumors.  The MZ ewsa/ewsa mutants displayed a higher percentage of cells with aneuploidy at 27 hpf, compared to wildtype zebrafish.  These results suggest that Ewsa maintains chromosomal stability.  Because Ewing sarcoma is often associated with an impaired P53 pathway, we further generated a double-mutant line by intercrossing ewsa/wt and tp53(M214K)/wt mutants.  As a result, the incidence of tumorigenesis in the tp53/wt;ewsa/ewsa line and the  tp53/wt;ewsa/wt line was higher than in the tp53/wt;wt/wt line. The result suggests that endogenous Ewsa inhibits tumorigenesis in tp53/wt zebrafish.  Moreover, the tumor samples obtained from (tp53/wt;ewsa/wt) or (tp53/wt;ewsa/ewsa) zebrafish were converted to (tp53/tp53;ewsa/wt) or (tp53/tp53;ewsa/ewsa).  The result suggests that zebrafish from the (tp53/wt) line developed tumors by undergoing LOH (Loss of Heterozygosity) to the (tp53/tp53), and wildtype Ewsa plays a role in inhibiting LOH induction.  Here, we propose that the loss of EWS allele as a result of formation of EWS-fusion gene may play a role in the pathogenesis of Ewing sarcoma development.



ZFIN Genetics Index
1. ewsr1a
2. tp53
3. fli1a
4. erg
5. etv1
6. etv4
7. fev