Abstract
Neuroblastoma is one of only a few human cancers that can spontaneously regress even after extensive dissemination, a poorly understood phenomenon that occurs in as many as 10% of patients. In this study, we identify the TALE-homeodomain transcription factor MEIS2 as a key contributor to this phenomenon. We identified MEIS2 as a MYCN-independent factor in neuroblastoma and showed that in this setting the alternatively spliced isoforms MEIS2A and MEIS2D exert antagonistic functions. Specifically, expression of MEIS2A was low in aggressive stage 4 neuroblastoma but high in spontaneously regressing stage 4S neuroblastoma. Moderate elevation of MEIS2A expression reduced proliferation of MYCN-amplified human neuroblastoma cells, induced neuronal differentiation and impaired the ability of these cells to form tumors in mice. In contrast, MEIS2A silencing or MEIS2D upregulation enhanced the aggressiveness of the tumor phenotype. Mechanistically, MEIS2A uncoupled a negative feedback loop that restricts accumulation of cellular retinoic acid, an effective agent in neuroblastoma treatment. Overall, our results illuminate the basis for spontaneous regression in neuroblastoma and identify an MEIS2A-specific signaling network as a potential therapeutic target in this common pediatric malignancy.Significance: This study illuminates the basis for spontaneous regressions that can occur in a common pediatric tumor, with implications for the development of new treatment strategies. Cancer Res; 78(8); 1935-47. ©2018 AACR.
Highlights
Alternative splicing, the combinatorial use of protein coding exons during the maturation of pre-mRNA to mRNA, facilitates expression of multiple mRNA isoforms from the same gene, greatly expanding the protein repertoire in a given cell
Upon categorization according to the five prognostic INSS stages, MEIS2 mRNA expression was lowest in high-risk st3 and st4 tumors, but highest in st4S tumors (Fig. 1D; Supplementary Fig. S1B)
Childhood cancer mortality from neuroblastoma has been declining during the last decade, the harsh multimodal therapy currently used to treat high-risks neuroblastoma has severe side effects for most surviving patients [36, 37]
Summary
Alternative splicing, the combinatorial use of protein coding exons during the maturation of pre-mRNA to mRNA, facilitates expression of multiple mRNA isoforms from the same gene, greatly expanding the protein repertoire in a given cell. Over 90% of multiexon genes are subject to alternative splicing, and the number of different splice isoforms synthesized from a single gene can vary between few and several thousands [1]. Genome-wide transcriptome profiling of normal and diseased. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Kolb: Dr Ehrlich Pharma, D-88410 Bad Wurzach, Germany; and current address for A. Khilan: College of Science and Engineering, Hamad bin Khalifa University, Doha, Qatar
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