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A heritable polymorphism within regulatory sequences of the  LMO1  gene is associated with its elevated expression and increased susceptibility to develop neuroblastoma, but the oncogenic pathways downstream of the LMO1 transcriptional co-regulatory protein are unknown. Our ChIP-seq and RNA-seq analyses reveal that a key gene directly regulated by LMO1 and MYCN is  ASCL1 , which encodes a basic helix-loop-helix transcription factor. Regulatory elements controlling  ASCL1  expression are bound by LMO1, MYCN and the transcription factors GATA3, HAND2, PHOX2B, TBX2 and ISL1—all members of the adrenergic (ADRN) neuroblastoma core regulatory circuitry (CRC).  ASCL1  is required for neuroblastoma cell growth and arrest of differentiation.  ASCL1  and  LMO1  directly regulate the expression of CRC genes, indicating that  ASCL1  is a member and  LMO1  is a coregulator of the ADRN neuroblastoma CRC.

ASCL1 is a MYCN- and LMO1-dependent member of the adrenergic neuroblastoma core regulatory circuitry