High delta‐like 1 expression in a subset of neuroblastoma cell lines corresponds to a differentiated chromaffin cell type

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Abstract
The childhood tumour neuroblastoma originates from neural crest-derived progenitors of the sympathetic nervous system. By Serial Analysis of Gene Expression (SAGE), we previously identified the Drosophila Delta homologue Dlk1 as one of the genes most highly expressed in the neuroblastoma cell line SK-N-FI. The Delta-Notch pathway controls many differentiation steps in Drosophila and man. We analysed expression of 21 genes of this pathway in 21 neuroblastoma cell lines. Dlk1 expression was very high in 5 cell lines, while another subset expressed Notch3. The imprinting of Dlk1 was faithfully preserved in neuroblastomas. The single paternal allele can therefore produce over 0.5% of all cellular mRNAs. Dlk1 maps to 14q32, a region that exhibited LOH in 31/170 (18%) tumours. The random parental origin of the deleted alleles excluded Dlk1 as target of the LOH. In addition, Dlk1 was not amplified, rearranged or mutated in neuroblastoma cell lines and tumours. We therefore analysed whether high Dlk1 expression marks a specific differentiation stage of the sympatho-adrenal lineage. Many neuroblastomas arise in the adrenal medulla, which predominantly consists of chromaffin cells. Normal adrenal medulla exhibited equally high Dlk1 levels as the SK-N-FI cell line. Chromaffin cells in young children are marked by noradrenalin production, which is mediated by dopamine-beta-hydroxylase (DBH). DBH expression in the neuroblastoma cell lines almost perfectly corresponded to Dlk1 expression. Neuroblastoma cell lines with high Dlk1 expression are therefore arrested in a relatively late stage of chromaffin lineage differentiation, while Notch3 expression might correspond to earlier precursor stages or to an alternative developmental fate.