BioProject

Amplification of the MYCN oncogene predicts treatment resistance in childhood neuroblastoma. More...

Amplification of the MYCN oncogene predicts treatment resistance in childhood neuroblastoma. Using a MYC target gene signature that predicts poor neuroblastoma prognosis we identified the histone chaperone, FAcilitates Chromatin Transcription (FACT), as a crucial mediator of the MYC signal and a therapeutic target in the disease. FACT and MYCN expression created a forward feedback loop in neuroblastoma cells that was essential for maintaining mutual high expression. FACT inhibition by the small molecule Curaxin compound, CBL0137, markedly reduced tumor initiation and progression in vivo. CBL0137 exhibited strong synergy with chemotherapy in standard use by blocking repair of DNA damage caused by genotoxic drugs, thus creating a synthetic lethal environment in MYCN amplified neuroblastoma cells and a treatment strategy for MYCN-driven neuroblastoma Overall design: BE(2)C neuroblastoma cells were transfected with either control non-targeting siRNA's or siRNA's directed against MYCN. 36 hours post-transfection, RNA was isolated for hybridisation on Affymetrix Human Gene 2.0 ST arrays. Less...