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

Nat Commun. 2019 Dec 09;10(1):5622
Lu Wang 1 , Tze King Tan 2 , Adam D Durbin 3 , Mark W Zimmerman 4 , Brian J Abraham 5 , Shi Hao Tan 2 , Phuong Cao Thi Ngoc 2 , Nina Weichert-Leahey 6 , Koshi Akahane 7 , Lee N Lawton 8 , Jo Lynne Rokita 9 , John M Maris 10 , Richard A Young 11 , A Thomas Look 12 , Takaomi Sanda 13
Lu Wang 1 , Tze King Tan 2 , Adam D Durbin 3 , Mark W Zimmerman 4 , Brian J Abraham 5 , Shi Hao Tan 2 , Phuong Cao Thi Ngoc 2 , Nina Weichert-Leahey 6 , Koshi Akahane 7 , Lee N Lawton 8 , Jo Lynne Rokita 9 , John M Maris 10 , Richard A Young 11 , A Thomas Look 12 , Takaomi Sanda 13
+ et al

[No authors listed]

Author information
  • 1 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore.
  • 2 Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
  • 3 The Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
  • 4 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02216, USA.
  • 5 Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38102, USA.
  • 6 Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02215, USA.
  • 7 Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, 4093898, Japan.
  • 8 Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA.
  • 9 Department of Bioinformatics and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
  • 10 Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 11 Biology Department, MIT, Cambridge, MA, 02142, USA.
  • 12 Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02215, USA. thomas_look@dfci.harvard.edu.
  • 13 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore. takaomi_sanda@nus.edu.sg.

摘要

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.

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