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PTEN  promoter hypermethylation is nearly universal and  PTEN  copy number loss occurs in ~25% of fusion-negative rhabdomyosarcoma (FN-RMS). Here we show  Pten  deletion in a mouse model of FN-RMS results in less differentiated tumors more closely resembling human embryonal RMS. PTEN loss activated the PI3K pathway but did not increase mTOR activity. In wild-type tumors, PTEN was expressed in the nucleus suggesting loss of nuclear PTEN functions could account for these phenotypes.  Pten  deleted tumors had increased expression of transcription factors important in neural and skeletal muscle development including  Dbx1  and  Pax7 .  Pax7  deletion completely rescued the effects of  Pten  loss. Strikingly, these  Pten;Pax7  deleted tumors were no longer FN-RMS but displayed smooth muscle differentiation similar to leiomyosarcoma. These data highlight how  Pten  loss in FN-RMS is connected to a PAX7 lineage-specific transcriptional output that creates a dependency or synthetic essentiality on the transcription factor PAX7 to maintain tumor identity.

Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity