ABSTRACT
1Dept. of Chemical, Food, Pharmaceutical and Pharmacological Sciences, University of Piemonte Orientale A. Avogadro, Novara, Italy
2 Molecular Haematology and Cancer Biology Unit, UCL Institute of Child Health, London, UK
Neuroblastoma is the most common extracranial solid tumor of childhood, characterized by the cancerous transformation of immature, neural crest-derived, sympathetic neuroblasts, which have lost their ability to differentiate into mature cells.
One of the most important genetic aberrations responsible for neuroblastoma is the amplification of the MYCN oncogene.
In this study we have identified the transcription factor BMYB, involved in cell proliferation and cell cycle regulation, as a downstream target of MYCN.
Indeed, we demonstrated that BMYB is overexpressed only in the MYCN-amplified neuroblastoma cell lines and it is essentially required for their proliferation.
Interestingly, MYCN binds to and activates the BMYB gene in vivo and in vitro. On the other side, BMYB binds in vivo to the MYCN amplicon and it is required for its expression.
These results suggest a reciprocal regulatory loop between MYCN and BMYB, whose pharmacological targeting may represent a new approach to the therapy of the aggressive forms of neuroblastoma, in which MYCN is amplified.
To this purpose, we screened a library of synthetic and natural compounds that allowed us to identify inhibitors of BMYB which will be used in preclinical tests in mouse models of neuroblastoma.