The Requirement for Evasion of Programmed Cell Death in Neuroblastomas with MYCN Amplification

Neuroblastoma is a tumour of the peripheral nervous system that accounts for 15% of cancer-related deaths in childhood. Amplification and overexpression of the MYCN proto-oncogene occurs in 25% of neuroblastomas and is highly correlated with treatment failure and mortality. MYCN stimulates cell cycle entry but does not alleviate the requirement for ongoing mitogenic signalling to support this proliferation. In fact, deregulated MYCN potently heightens cell sensitivity to myriad stressors that induce programmed cell death, although the mechanisms of this effect are poorly understood. To circumvent this safeguard against oncogene-driven neoplasia, cancer cells with deregulated MYC frequently exhibit defects in apoptotic pathways. It is similarly proposed that neuroblasts with MYCN amplification have obligate defects in pathways that engage or execute apoptosis, and these defects contribute to the malignant phenotype. Investigations into the molecular genetics of both primary human neuroblastomas with MYCN amplification, as well as tumours arising in genetically engineered mice with targeted MYCN overexpression, should help to define these cooperating genetic lesions. Elucidating the mechanisms whereby non-transformed neural cells engage MYCN-primed apoptosis, as well as the mechanisms neuroblasts with MYCN amplification use to evade this process, will define useful targets for biological therapeutics that exploit the inherent apoptosis-priming function of deregulated MYCN.