11q Deletion or ALK Activity Curbs DLG2 Expression to Maintain an Undifferentiated State in Neuroblastoma
Joachim Tetteh Siaw,
Niloufar Javanmardi,
Jimmy Van den Eynden,
Dan Emil Lind,
Susanne Fransson,
Angela Martinez-Monleon,
Anna Djos,
Rose-Marie Sjöberg,
Malin Östensson,
Helena Carén,
Gunhild Trøen,
Klaus Beiske,
Ana P. Berbegall,
Rosa Noguera,
Wei-Yun Lai,
Per Kogner,
Ruth H. Palmer,
Bengt Hallberg,
Tommy Martinsson
Affiliations
Joachim Tetteh Siaw
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
Niloufar Javanmardi
Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530 Gothenburg, Sweden
Jimmy Van den Eynden
Department of Human Structure and Repair, Anatomy and Embryology Unit, Ghent University, 9000 Ghent, Belgium
Dan Emil Lind
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
Susanne Fransson
Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530 Gothenburg, Sweden
Angela Martinez-Monleon
Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530 Gothenburg, Sweden
Anna Djos
Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530 Gothenburg, Sweden
Rose-Marie Sjöberg
Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530 Gothenburg, Sweden
Malin Östensson
Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
Helena Carén
Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Gunhild Trøen
Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Pathology, Oslo University Hospital, Oslo, Norway
Klaus Beiske
Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Pathology, Oslo University Hospital, Oslo, Norway
Ana P. Berbegall
Department of Pathology, Medical School, University of Valencia/INCLIVA, Valencia/CIBER of Cancer, Madrid, Spain
Rosa Noguera
Department of Pathology, Medical School, University of Valencia/INCLIVA, Valencia/CIBER of Cancer, Madrid, Spain
Wei-Yun Lai
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
Per Kogner
Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
Ruth H. Palmer
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; Corresponding author
Bengt Hallberg
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; Corresponding author
Tommy Martinsson
Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530 Gothenburg, Sweden; Corresponding author
Summary: 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.
