A recent study has revealed new insights into the mechanisms behind neuroblastoma (NB), the most common extracranial childhood cancer. Researchers focused on the role of a specific epitranscriptomic modification, N6-methyladenosine (m6A), which regulates gene expression and could hold the key to more effective treatments for NB.
Neuroblastoma, often associated with amplification of the MYCN oncogene, is characterised by the undifferentiated state of trunk neural crest cells (tNCC) that fail to develop into mature sympathetic neurons. The study demonstrated that m6A modification controls the expression of key HOX genes in tNCC, which are crucial for their proper differentiation. However, in MYCN-amplified NB, m6A modification of posterior HOX genes is reduced, contributing to the undifferentiated state that defines the cancer’s aggressive nature.
Importantly, the study revealed that the overexpression of MYCN recruits the METTL3 methyltransferase complex to specific genes, including HOX genes, thus preventing proper differentiation. The researchers found that depleting or inhibiting METTL3 in MYCN-overexpressing cells led to increased DNA damage, promoted differentiation, and heightened the cells’ sensitivity to chemotherapy.
These findings suggest that targeting METTL3 could provide a promising therapeutic strategy for treating MYCN-driven neuroblastoma. In animal models, METTL3 inhibition not only induced differentiation but also increased the efficacy of chemotherapy, offering hope for more effective treatments for this challenging childhood cancer.
Reference
Thombare K et al. METTL3/MYCN cooperation drives neural crest differentiation and provides therapeutic vulnerability in neuroblastoma. J EMBO. 2024.
