The role of the homeobox transcription factor Duxbl in rhabdomyosarcoma formation

Skeletal muscles exhibit a remarkable regeneration capacity that is mediated by resident muscle stem cells (MuSCs). While normally quiescent they become activated upon injury, proliferate and differentiate into myofibers to repair damaged skeletal muscle. Rhabdomyosarcoma (RMS) tumors show features of skeletal muscle differentiation. Previous studies revealed that RMS tumors form at high incidence in mdx mice that undergo chronic muscle regeneration. However, unequivocal proofs on the cellular origin of these RMS tumors are lacking. Consequently, the underlying molecular mechanism of how RMS tumors are formed remain poorly understood. In this study, I show that MuSC-specific deletion of the tumor suppressor p53 is sufficient to induce formation of fluorescently lineage traced RMS tumorsin conditions of chronic muscle regeneration when MuSCs are activated. The genetic lineage tracing approach demonstrated that MuSCs are the origin of RMS tumors in these mice. Importantly, the tracing approach also enabled separation of cells from RMS tumors that are either derived from transformed MuSC descendants or from stromal cells of non-MuSC origin. Whole-exome sequencing performed on these purified tumor cell populations from different tumors revealed discrete oncogenic copy number amplifications (CNA) associated with MuSC-derived RMS tumor formation. I performed a comprehensive analysis on the function of a poorly investigated gene encoding for a putative transcriptional regulator called Duxbl,because this gene was recurrently amplified in many of the exome-sequenced RMS tumors. Inactivation of Duxblin tumor cells harboring a Duxbl CNA resulted in cell death, indicating that Duxbl plays an important role in both promotion and maintenance of Duxbl-associated RMS tumors. In contrast, overexpression of Duxbl in MuSCs resulted in enhanced proliferation and inhibited myogenic differentiation. I generated a mouse model enabling conditional overexpression of Duxbl and found that induction of Duxbl in p53-deficient MuSCs is sufficient to induce RMS tumor formation in vivo, proving that Duxblcan function as an oncogene. I discovered that overexpression of Duxbl inconjunction with p53inactivation inducesexpression of endogenous retrotransposons of the ERVL subclass and that ERVL is specially re-activated in Duxbl-induced RMS tumors. This study identifies Duxbl as a novel oncogene that is able to promote RMS tumor formation in p53-deficient MuSCs, probably by activation of ERVL.

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The role of the homeobox transcription factor Duxbl in rhabdomyosarcoma formation

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