METTL3/MYCN cooperation drives neural crest differentiation and provides therapeutic vulnerability in neuroblastoma

• DOI: 10.1101/2023.10.06.561194
• Publication Date: 2023-10-09T07:59:23Z
• Authors: Ketan Thombare; Roshan Vaid; Perla Pucci; Akram Mendez; Rebeca Burgos-Pan...; Ritish Ayyalusamy; Aqsa Ali Rehan; Mohammad Hassan Baig; Sagar Dattatraya ...; Christoph Bartenh...; Jae-June Dong; Matthias Fischer; Suzanne D. Turner; Tanmoy Mondal

Abstract Neuroblastoma (NB) is the most common extracranial childhood cancer, caused by improper differentiation of developing trunk neural crest cells (tNCC) in sympathetic nervous system. The N 6 -methyladenosine (m A) epitranscriptomic modification controls post-transcriptional gene expression but mechanism which m A methyltransferase complex METTL3/METTL14/WTAP recruited to specific loci remains be fully characterized. We explored whether epitranscriptome could fine-tune regulation migrating/differentiating tNCC. demonstrate that regulates HOX genes tNCC, thereby contributing their timely into neurons. Furthermore, we show posterior are modified MYCN-amplified NB with reduced expression. In addition, provide evidence sustained overexpression MYCN oncogene tNCC drives METTL3 recruitment a subset including creating an undifferentiated state. Moreover, depletion/inhibition induces DNA damage and overexpressing increases vulnerability chemotherapeutic drugs patient-derived xenografts (PDX) cells, suggesting inhibition potential therapeutic approach for NB.