Mice null for the deubiquitinase USP18 spontaneously develop leiomyosarcomas

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Ubiquitin-specific protease 18 (USP18) deconjugates ISG15 from proteins.
• USP18 deficiency in FVB/N mice leads to spontaneous tumor development.
• These tumors represent a novel murine model for leiomyosarcoma.

Purpose of the Study:

• To characterize the leiomyosarcomas arising in USP18 null mice.
• To investigate the role of USP18 in leiomyosarcoma development and progression.
• To evaluate USP18 expression in human leiomyosarcomas and its clinical significance.

Main Methods:

• Breeding of heterozygous USP18+/- FVB/N mice to generate experimental cohorts.
• Immunohistochemical and karyotypic analysis of tumors and derived cell lines.
• Assessment of USP18 activity restoration and drug sensitivity in cell lines.
• Analysis of USP18 expression in human leiomyosarcoma patient samples.

Main Results:

• USP18-/- FVB/N mice exhibit 80% penetrance of leiomyosarcomas by 12 months.
• Tumor-derived cell lines were aneuploid with MYC amplification, a feature shared with human leiomyosarcomas.
• Reduced USP18 levels in human leiomyosarcomas correlated with significantly decreased time to metastasis (P=0.0441).

Conclusions:

• USP18 null mice provide a clinically relevant model for studying leiomyosarcoma.
• The study highlights key genetic alterations, including MYC amplification, in leiomyosarcoma.
• Reduced USP18 expression is associated with poor prognosis in leiomyosarcoma patients, indicating therapeutic potential.