Research Article: Epigenetic Features of Human Mesenchymal Stem Cells Determine Their Permissiveness for Induction of Relevant Transcriptional Changes by SYT-SSX1

Date Published: November 19, 2009

Publisher: Public Library of Science

Author(s): Luisa Cironi, Paolo Provero, Nicola Riggi, Michalina Janiszewska, Domizio Suva, Mario-Luca Suva, Vincent Kindler, Ivan Stamenkovic, Stefan Wölfl.

Abstract: A characteristic SYT–SSX fusion gene resulting from the chromosomal translocation t(X;18)(p11;q11) is detectable in almost all synovial sarcomas, a malignant soft tissue tumor widely believed to originate from as yet unidentified pluripotent stem cells. The resulting fusion protein has no DNA binding motifs but possesses protein-protein interaction domains that are believed to mediate association with chromatin remodeling complexes. Despite recent advances in the identification of molecules that interact with SYT-SSX and with the corresponding wild type SYT and SSX proteins, the mechanisms whereby the SYT-SSX might contribute to neoplastic transformation remain unclear. Epigenetic deregulation has been suggested to be one possible mechanism.

Partial Text: Synovial sarcoma (SS) is an aggressive soft tissue tumor that accounts for about 10% of all human sarcomas [1]–[3] and is found throughout the body. It arises in adolescents and young adults and is associated with poor prognosis despite multimodal therapy. Current opinion holds that sarcomas, including synovial sarcoma, are derived from as yet unidentified multipotent stem cells capable of mesenchymal and neuroectodermal differentiation.

We have analyzed the transcriptional effects of SYT-SSX1 expression in bone marrow derived human mesenchymal stem cells isolated from pediatric or adolescent patients. These cells may provide an appropriate model to study synovial sarcoma development, based on the generally recognized notion that SS originates from as yet unidentified pluripotent stem cells capable of mesenchymal and neuroectodermal differentiation. The only available transgenic model of SS [14] thus far, suggests that development of SS is linked to the expression of the early myogenic marker Myf5. Co-expression of early markers for different tissue lineages has been observed in MSCs [58], without necessarily being associated with loss of plasticity. Human MSC expressed Myf5 with up to a 30-fold population-dependent transcript level variation (data not shown). However, we could not establish whether the observed differences in expression were due to varying enrichment of a specific sub-population or to homogeneous, donor specific, traits.



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