High-risk 11q deleted neuroblastomas typically display undifferentiated/poorly differentiated morphology. Neuroblastoma is thought to develop from Schwann cell precursors and undifferentiated neural crest (NC) derived cells. It is therefore vital to understand mechanisms involved in the block of differentiation. We identify an important role for oncogenic ALK-ERK1/2-SP1 signaling in maintenance of undifferentiated NC-derived progenitors via repression of DLG2, a tumor suppressor in neuroblastoma. DLG2 is expressed in the ‘bridge signature’ that represents the transcriptional transition state when neural crest cells or Schwann Cell Precursors become chromaffin cells of the adrenal gland. We show that restoration of DLG2 expression spontaneously drives neuroblastoma differentiation highlighting the importance of DLG2 in this process. Further, genetic analysis of high-risk 11q-deletion neuroblastomas 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 neuroblastoma.
Siaw, Joachim and Javanmardi, Niloufar and Van den Eynden, Jimmy and Lind, Dan Emil and Fransson, Susanne and Marinez-Monleon, Angela and Djos, Anna and Sjöberg, Rose-Marie and Östensson, Malin and Carén, Helena and Trøen, Gunhild and Beiske, Klaus and Bergegall, Ana and Noguera, Rosa and Lai, Wei-Yun and Kogner, Per and Palmer, Ruth H. and Hallberg, Bengt and Martinsson, Tommy, 11q Deletion or ALK Activity Curbs DLG2 Expression to Maintain an Undifferentiated State in Neuroblastoma. Available at SSRN: https://ssrn.com/abstract=3571291 or http://dx.doi.org/10.2139/ssrn.3571291
This version of the paper has not been formally peer reviewed.
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