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Appearance of the novel activating F1174S ALK mutation in neuroblastoma correlates with aggressive tumor progression and unresponsiveness to therapy
- Source :
- Cancer research. 71(1)
- Publication Year :
- 2010
-
Abstract
- 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 behavior. 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 2 independent systems. First, PC12 cell lines expressing ALKF1174S display ligand-independent activation of ALK and further downstream signaling activation. Second, 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 that 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 analysis, in particular in tumor progression and/or tumor relapse, is warranted for better understanding of the treatment of neuroblastoma patients. Cancer Res; 71(1); 98–105. ©2011 AACR.
- Subjects :
- Male
Cancer Research
Mutant
Biology
PC12 Cells
Polymorphism, Single Nucleotide
Mice
Neuroblastoma
hemic and lymphatic diseases
medicine
Anaplastic lymphoma kinase
Animals
Humans
Anaplastic Lymphoma Kinase
DNA Primers
Base Sequence
Kinase
Gene Expression Profiling
Wild type
Infant
Receptor Protein-Tyrosine Kinases
Protein-Tyrosine Kinases
medicine.disease
Immunohistochemistry
Rats
Oncology
Protein kinase domain
Tumor progression
Mutation
Cancer research
Disease Progression
NIH 3T3 Cells
Signal transduction
Signal Transduction
Subjects
Details
- ISSN :
- 15387445
- Volume :
- 71
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Cancer research
- Accession number :
- edsair.doi.dedup.....ce6970724758ae3decd9f37977ab464e