Appearance of the novel activating F1174S ALK mutation in neuroblastoma correlates with aggressive tumour progression and unresponsiveness to therapy
2011 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 71, no 1, 98-105 p.Article in journal (Other academic) Published
Mutations in the kinase domain of the ALK kinase have emerged recently as important players in the genetics of the childhood tumor neuroblastoma. Here we report the appearance of a novel ALK mutation in neuroblastoma, correlating with aggressive tumor behaviour. Analyses of genomic DNA from biopsy samples initially showed ALK sequence to be wild type. However, during disease progression mutation of amino acid F1174 to a serine within the ALK kinase domain was observed, which correlated with aggressive neuroblastoma progression in the patient. We show that mutation of F1174 to serine generates a potent gain-of-function mutant, as observed in two independent systems. Firstly, PC12 cell lines expressing ALKF1174S display ligand independent activation of ALK and further downstream signaling activation. Secondly, analysis of ALKF1174S in Drosophila models confirms that the mutation mediates a strong rough eye phenotype upon expression in the developing eye. Thus, we report a novel ALKF1174S mutation, which displays ligand independent activity in vivo, correlating with rapid and treatment resistant tumor growth. The study also shows that initial screening in the first tumor biopsy of a patient may not be sufficient and that further molecular analyses in particular in tumor progression and/or tumor relapse is warranted for better understanding of the treatment of neuroblastoma patients.
Place, publisher, year, edition, pages
American Association for Cancer Research , 2011. Vol. 71, no 1, 98-105 p.
ALK, neuroblastoma, gain of function
Cell and Molecular Biology
Research subject Molecular Biology
IdentifiersURN: urn:nbn:se:umu:diva-36978DOI: 10.1158/0008-5472.CAN-10-2366OAI: oai:DiVA.org:umu-36978DiVA: diva2:356944
ProjectsExploiting Drosophila as a model system for studying Anaplastic Lymphoma Kinase in vivo