JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells

Rhabdomyosarcomas (RMS) are the most frequent soft-tissue sarcoma in children and

associated with a PAX3-FOXO1 fusion protein that is known to contribute to the undifferentiated

processes in both normal and malignant cell contexts. Here we show that JARID2, that encodes a

is significantly overexpressed in RMS with PAX3-FOXO1 compared to fusion gene negative RMS

metastases at diagnosis, independent of fusion gene status and RMS subtype (n= 120; p=0.039).

and without the fusion gene, respectively. Consistent with this, we demonstrated that JARID2 is a

reduced cell proliferation coupled with myogenic differentiation including increased expression of

both the alveolar and embryonal subtypes. Induced myogenic differentiation was associated with a

Furthermore, we that showed JARID2 binds to and alters the methylation status of histone H3

promoters is dependent upon EED, a core component of the Polycomb Repressive Complex 2

(PRC2). Therefore JARID2 is a downstream effector of PAX3-FOXO1 that maintains an undifferentiated myogenic phenotype that is characteristic of RMS. JARID2 and other components of PRC2 may represent novel therapeutic targets for treating RMS patients.