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Establishment and characterization of MRT cell lines from genetically engineered mouse models and the influence of
Yasumichi Kuwahara1, E Lorena Mora-Blanco, Fatima Banine
1UNC-Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295, USA. weissman@med.unc.edu
Abstract:
Malignant rhabdoid tumors (MRTs) are rare, aggressive cancers occuring in young children primarily through inactivation of the SNF5(INI1, SMARCB1) tumor suppressor gene. We and others have demonstrated that mice heterozygous for a Snf5 null allele develop MRTs with partial penetrance. We have also shown that Snf5(+/-) mice that lack expression of the pRb family, due to TgT121 transgene expression, develop MRTs with increased penetrance and decreased latency. Here, we report that altering the genetic background has substantial effects upon MRT development in Snf5(+/--) and TgT121 ;Snf5(+/-) mice, with a mixed F1 background resulting in increased latency and the appearance of brain tumors. We also report the establishment of the first mouse MRT cell lines that recapitulate many features of their human counterparts. Our studies provide further insight into the genetic influences on MRT development as well as provide valuable new cell culture and genetically engineered mouse models for the study of CNS-MRT etiology.
Insights
Genetic background significantly impacts malignant rhabdoid tumor (MRT) development in mice. New cell lines and models offer insights into these aggressive childhood cancers.
Area of Science:
- Oncology
- Genetics
- Developmental Biology
Background:
- Malignant rhabdoid tumors (MRTs) are rare, aggressive pediatric cancers.
- SNF5 (INI1, SMARCB1) tumor suppressor gene inactivation is a primary driver of MRTs.
- Previous studies showed Snf5(+/-) mice develop MRTs with partial penetrance.
Purpose of the Study:
- Investigate the impact of genetic background on MRT development.
- Explore the role of pRb family expression in MRTs.
- Establish novel mouse MRT cell lines for research.
Main Methods:
- Utilized genetically engineered mouse models (Snf5(+/-) and TgT121;Snf5(+/-)).
- Altered genetic backgrounds (mixed F1) to assess tumor development.
- Established and characterized new MRT cell lines.
Main Results:
- Genetic background significantly influenced MRT latency and tumor type.
- A mixed F1 background increased latency and led to brain tumor development.
- Established the first mouse MRT cell lines mirroring human disease features.
Conclusions:
- Genetic background is a critical factor in MRT pathogenesis.
- TgT121;Snf5(+/-) mice on specific backgrounds are valuable models for MRT research.
- New cell lines provide essential tools for studying MRT etiology, particularly CNS-MRTs.
