11q Deletion or ALK Activity Curbs DLG2 Expression to Maintain an Undifferentiated State in Neuroblastoma

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. [Display omitted] •ALK-ERK-SP1 signaling promotes an undifferentiated state in neuroblastoma cells•ALK signaling suppresses DLG2 transcription•DLG2 expression drives differentiation of neuroblastoma cells•11q deletion neuroblastomas exhibit genetic lesions in the DLG2 locus Siaw et al. show that oncogenic ALK-ERK1/2-SP1 signaling maintains neuroblastoma cells in an undifferentiated state through the suppression of DLG2 transcription. The expression of DLG2 drives differentiation and inhibits tumor growth. Genetic analysis of high-risk 11q deletion neuroblastoma identifies genetic lesions in the DLG2 gene in patient samples.