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Anaplastic Lymphoma Kinase (ALK) regulates initiation of transcription of MYCN in neuroblastoma cells

Artikel i vetenskaplig tidskrift
Författare C. Schönherr
K. Ruuth
S. Kamaraj
C. L. Wang
H. L. Yang
V. Combaret
Anna Djos
Tommy Martinsson
J. G. Christensen
R. H. Palmer
B. Hallberg
Publicerad i Oncogene
Volym 31
Nummer/häfte 50
Sidor 5193-5200
ISSN 0950-9232
Publiceringsår 2012
Publicerad vid Institutionen för biomedicin, avdelningen för medicinsk genetik och klinisk genetik
Sidor 5193-5200
Språk en
Länkar dx.doi.org/10.1038/onc.2012.12
Ämnesord neuroblastoma, anaplastic lymphoma kinase, ALK, MYCN, transcription factor, n-myc, tyrosine kinase, lung-cancer, activating mutations, c-myc, inhibitors, expression, protein, crizotinib, receptor
Ämneskategorier Genetik, Medicinsk genetik

Sammanfattning

Neuroblastoma is a neural crest-derived embryonal tumour of the postganglionic sympathetic nervous system and a disease with several different chromosomal gains and losses, which include MYCN-amplified neuroblastoma on chromosome 2, deletions of parts of the chromosomes 1p and 11q, gain of parts of 17q and triploidy. Recently, activating mutations of the ALK (Anaplastic Lymphoma Kinase) RTK (Receptor Tyrosine Kinase) gene have been described in neuroblastoma. A meta-analysis of neuroblastoma cases revealed that ALK mutations (49 of 709 cases) in relation to genomic subtype were most frequently observed in MYCN amplified tumours (8.9%), correlating with a poor clinical outcome. MYCN proteins target proliferation and apoptotic pathways, and have an important role in the progression of neuroblastoma. Here, we show that both wild-type and gain-of-function mutants in ALK are able to stimulate transcription at the MYCN promoter and initiate mRNA transcription of the MYCN gene in both neuronal and neuroblastoma cell lines. Further, this stimulation of MYCN gene transcription and de novo MYCN protein expression is abrogated by specific ALK inhibitors, such as crizotinib (PF-2341066), NVP-TAE684, and by small interfering RNA to ALK resulting in a decrease in proliferation rate. Finally, co-transfection of ALK gain-of-function mutations together with MYCN leads to an increase in transformation potential. Taken together, our results indicate that ALK signalling regulates initiation of transcription of the MYCN gene providing a possible explanation for the poor clinical outcome observed when MYCN is amplified together with activated ALK.

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