Abstract
High-risk neuroblastomas typically display an undifferentiated or poorly differentiated morphology. It is therefore vital to understand molecular mechanisms that block the differentiation process. We identify an important role for oncogenic ALK-ERK1/2-SP1 signaling in the maintenance of undifferentiated neural crest-derived progenitors through the repression of DLG2, a candidate tumor suppressor gene in neuroblastoma. DLG2 is expressed in the murine "bridge signature" that represents the transcriptional transition state when neural crest cells or Schwann cell precursors differentiate to chromaffin cells of the adrenal gland. We show that the restoration of DLG2 expression spontaneously drives neuroblastoma cell differentiation, highlighting the importance of DLG2 in this process. These findings are supported by genetic analyses of high-risk 11q deletion neuroblastomas, which identified genetic lesions in the DLG2 gene. Our data also suggest that further exploration of other bridge genes may help elucidate the mechanisms underlying the differentiation of NC-derived progenitors and their contribution to neuroblastomas.
Highlights
Pediatric neuroblastoma (NB) is a heterogeneous disease, with differing prognosis depending on the subgroup
Furlan et al (2017) identified a unique set of murine genes expressed by transient intermediate cells they called bridge cells that arise during the differentiation of Schwann cell precursors (SCPs) to adrenal chromaffin cells (Figure 1A)
The high overall expression of early peak time bridge cell genes in NB patient tumor material strongly correlated with poor prognosis, while high expression of late peak time bridge cell genes correlated with better prognosis
Summary
Pediatric neuroblastoma (NB) is a heterogeneous disease, with differing prognosis depending on the subgroup. NB is characterized by multiple somatic chromosomal lesions at the genetic level, including structural variations (SVs) and copy-number alterations (CNAs). The common genetic features of NB include deletion of chromosome arm 1p, gain of parts of 17q, aneuploidy and amplification of the protooncogene MYCN, and deletion of parts of chromosome arm 11q, which are used to distinguish between high- and low-risk NB (Brodeur, 2003; Caren et al, 2008, 2010; De Brouwer et al, 2010; Hoehner et al, 1996; Maris, 2010; Park et al, 2013; Pugh et al, 2013). Unbalanced chromosomal alterations affecting 11q have been known for some time, no single candidate gene has been confirmed to play a role in NB despite intensive investigation, including thorough deletion mapping of this crucial region (11q14–q24) (Caren et al, 2008, 2010; Srivatsan et al, 1993)
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