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16 April 1998, Volume 16, Number 15, Pages 1973-1979
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Article
The desmoplastic small round cell tumor t(11;22) translocation produces EWS/WT1 isoforms with differing oncogenic properties
Jungho Kim1, Kevin Lee2 and Jerry Pelletier1,3,a

1Department of Biochemistry, McGill University, 3655 Drummond Street, Montreal, Quebec, Canada, H3G 1Y6

2Department of Biology, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong

3Department of Oncology, McGill University, 3655 Drummond Street, Montreal, Quebec, Canada, H3G 1Y6

aAuthor for correspondence:

Abstract

Structural alterations of the Wilms' tumor locus (WT1) at 11p13 have been implicated in the etiology of two human cancers - Wilms' tumor (WT), a pediatric renal malignancy, and Desmoplastic Small Round Cell Tumor (DSRCT), an aggressive cancer of the abdomenal serosal lining with predilection for male adolescents. Germline mutations within the WT1 tumor suppressor gene predispose to WT and are associated with congenital malformations of the urogenital system, and somatic mutations are associated with initiation of transformation in WTs. In DSRCT, a recurrent translocation, t(11;22)(p13;q12), fuses the amino terminal domain of the EWS1 gene product to three of the four WT1 zinc fingers. Two EWS/WT1 isoforms are generated as a result of an alternative splicing event between zinc fingers III and IV, inserting or removing three amino acids (±KTS). We demonstrate that introduction of EWS/WT1(-KTS) into NIH3T3 cells causes their tumorigenic transformation as determined by: formation of transformed foci on a monolayer of cells; anchorage-independent growth; and tumor formation in nude mice. EWS/WT1(+KTS) showed no transforming potential in these assays. These results indicate the oncogenic effect of the t(11;22) translocation is mediated by the EWS/WT1(-KTS) isoform and that fusion of the EWS amino terminal domain to the WT1 DNA binding domain produces a chimeric product showing a gain of function.

Keywords

EWS; WT1; DSRCT; oncogene; transformation; cancer genetics

Received 9 September 1997; revised 11 November 1997; accepted 11 November 1997
16 April 1998, Volume 16, Number 15, Pages 1973-1979
Table of contents    Previous  Abstract  Next   Article  PDF