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Updated: Oct 18, 2026
Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Melanoma loss-of-function mutants in Xiphophorus caused by Xmrk-oncogene deletion and gene disruption by a
M Schartl1, U Hornung, H Gutbrod
1Department of Physiological Chemistry I, Theodor-Boveri Institute, Biocenter, University of Würzburg, D-97074 Würzburg, Germany. phch1@biozentrum.uni-wuerzburg.de
Abstract:
The overexpression of the Xmrk oncogene (ONC-Xmrk) in pigment cells of certain Xiphophorus hybrids has been found to be the primary change that results in the formation of malignant melanoma. Spontaneous mutant stocks have been isolated that have lost the ability to induce tumor formation when crossed with Xiphophorus helleri. Two of these loss-of-function mutants were analyzed for genetic defects in ONC-Xmrk's. In the lof-1 mutant a novel transposable element, TX-1, has jumped into ONC-Xmrk, leading to a disruption of the gene and a truncated protein product lacking the carboxyterminal domain of the receptor tyrosine kinase. TX-1 is obviously an active LTR-containing retrotransposon in Xiphophorus that was not found in other fish species outside the family Poeciliidae. Surprisingly, it does not encode any protein, suggesting the existence of a helper function for this retroelement. In the lof-2 mutant the entire ONC-Xmrk gene was found to be deleted. These data show that ONC-Xmrk is indeed the tumor-inducing gene of Xiphophorus and thus the critical constituent of the tumor (Tu) locus.
Insights
The Xmrk oncogene (ONC-Xmrk) drives melanoma formation in Xiphophorus fish. Genetic analysis revealed mutations in ONC-Xmrk, including a transposable element insertion and gene deletion, confirming its role in tumor development.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Overexpression of the Xmrk oncogene (ONC-Xmrk) in pigment cells is linked to malignant melanoma in Xiphophorus hybrids.
- Spontaneous mutant stocks lacking tumor-inducing ability were identified.
Purpose of the Study:
- To investigate the genetic defects in ONC-Xmrk in loss-of-function mutants.
- To confirm ONC-Xmrk as the causative agent of Xiphophorus tumors.
Main Methods:
- Analysis of two loss-of-function mutants (lof-1 and lof-2).
- Genetic characterization of mutations affecting the ONC-Xmrk gene.
- Identification of a novel transposable element, TX-1, in the lof-1 mutant.
Main Results:
- The lof-1 mutant showed disruption of ONC-Xmrk by the TX-1 retrotransposon, resulting in a truncated protein.
- The lof-2 mutant exhibited a complete deletion of the ONC-Xmrk gene.
- TX-1 is an active LTR-containing retrotransposon specific to Xiphophorus, lacking protein-coding capacity.
Conclusions:
- ONC-Xmrk is definitively identified as the tumor-inducing gene in Xiphophorus.
- These findings establish ONC-Xmrk as the critical component of the tumor (Tu) locus.
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