Differentiation Therapy for Rhabdoid Tumors

Malignant rhabdoid tumors are uncommon but extremely aggressive childhood sarcomas for which there is no adequate therapy. Since rhabdoid tumors are characterized by defects in mesenchymal progenitor cell differentiation, therapies that target and correct these defects and induce terminal differentiation are an attractive alternative to the cytotoxic therapies currently used to treat these tumors. However, little is known about the molecular changes that occur in rhabdoid tumors, which limits the development of targeted therapies.

We observed frequent expression of the HOXB13 gene in rhabdoid tumors. HOXB13 is known to play an important role in cell determination during embryogenesis but its potential role in sarcomagenesis has not been studied. Our data show that the silencing of HOXB13 in a rhabdoid tumor cell line facilitates differentiation of tumors into bone. Conversely, expression of HOXB13 in mesenchymal progenitor cell lines inhibits differentiation and promotes retention of stem cell characteristics. Additionally, we show that HOXB13 is involved in the epigenetic regulation of a chromatin state and the repression of osteogenic genes. These data indicate that HOXB13 may be responsible for the maintenance of an undifferentiated state in rhabdoid tumors. We propose that targeting HOXB13 or downstream effectors that are required for its function may induce a differentiation program in rhabdoid tumors with consequential loss of the malignant phenotype.