Alternative Splicing of the NF-Y Subunit, NF-YA, in Neuroblastoma Phenotype Heterogeneity.

Neuroblastomas (NBs) are aggressive, therapy-resistant embryonal tumors of neural crest origin, which despite low mutational burdens exhibit high intra-tumoral heterogeneity characterized by adrenergic, noradrenergic, mesenchymal and cancer stem cell (CSC)-like subpopulations. These phenotypes exhibit interconverting plasticity that reflect both stage of transformation during sympathoadrenal development and conditions within the tumor microenvironment. Chemotherapeutic agents promote adrenergic-to-mesenchymal conversion in NBs, which underpins drug resistance, post-therapeutic relapse, metastatic progression, and the plateauing of responses to advances in multimodal therapy. Improved understanding of the molecular mechanisms that regulate NB phenotypic plasticity is essential for identifying novel prognostic markers and potential therapeutic targets. In this article, following introductions into NB, molecular regulation of NB phenotypic plasticity, and the NF-Y transcription factor and its role in development and differentiation, we focus on alternative NF-YAl, NF-YAs and NF-YAx splicing of the NF-Y subunit, NF-YA, and the potential influence that different NF-YA isoforms have on NF-Y function and the NF-Y-transcription factor networks that impact NB cell phenotypes. Particular attention is paid to the novel extra short-form NF-YAx isoform, originally detected as the exclusive NF-YA isoform in a non-