ASCL1, ACTIVATED BY LMO1 AND MYCN ONCOGENE, IS A MASTER REGULATOR OF DIFFERENTIATION PROGRAM IN ADRENERGIC NEUROBLASTOMA

Abstract

Neuroblastoma is an embryonal tumor of the peripheral sympathetic nervous system. A heritable polymorphism within regulatory sequences of the LMO1 gene is associated with its elevated expression and increased susceptibility to develop neuroblastoma. Animal model studies demonstrated that LMO1 could synergize with oncoprotein MYCN. However, molecular pathways regulated by LMO1 in neuroblastoma cells have not been elucidated yet. ASCL1, which encodes a basic helix-loop-helix transcription factor, was identified as a key target of LMO1 and MYCN oncoprotein. ASCL1 was highly expressed in ADRN subtype of neuroblastoma. Importantly, depletion of ASCL1 sensitized neuroblastoma cells to retinoic acid treatment to induce differentiation, thus providing a novel insight for neuroblastoma differentiation therapy. Moreover, ASCL1 directly regulated the expression of other CRC genes. Taken together, ASCL1 is a critical downstream target of LMO1 and MYCN and is an integral member of the ADRN neuroblastoma CRC, essential for the formation of the feed-forward auto-regulatory loop that drives the oncogenic transcriptional program.