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Appearance of the n...
Appearance of the novel activating F1174S ALK mutation in neuroblastoma correlates with aggressive tumor progression and unresponsiveness to therapy.
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- Martinsson, Tommy, 1956 (author)
- Clinical Genetics, University of Gothenburg
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- Eriksson, Therese, 1980- (author)
- Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten)
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- Abrahamsson, Jonas, 1954 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för pediatrik,Institute of Clinical Sciences, Department of Pediatrics,Pediatrics, University of Gothenburg
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- Carén, Helena, 1979 (author)
- Clinical Genetics, University of Gothenburg
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- Hansson, Magnus (author)
- Umeå universitet,Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper,Institute of Clinical Sciences,Institutionen för medicinsk biovetenskap,Pathology, University of Gothenburg
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- Kogner, Per (author)
- Karolinska Institutet,Dept. of Women and Child Health, Karolinska Institutet
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- Kamaraj, Sattu (author)
- Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten)
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- Schönherr, Christina (author)
- Umeå universitet,Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet)
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- Weinmar, Joel (author)
- Umeå universitet,Institutionen för medicinsk biovetenskap
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- Ruuth, Kristina (author)
- Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten)
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- Palmer, Ruth (author)
- Umeå universitet,Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet)
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- Hallberg, Bengt, 1956 (author)
- Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten)
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(creator_code:org_t)
- American Association for Cancer Research, 2011
- 2011
- English.
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In: Cancer research. - : American Association for Cancer Research. - 1538-7445 .- 0008-5472. ; 71:1, s. 98-105
- Related links:
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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 ALK(F1174S) display ligand-independent activation of ALK and further downstream signaling activation. Second, analysis of ALK(F1174S) in Drosophila models confirms that the mutation mediates a strong, rough eye phenotype upon expression in the developing eye. Thus, we report a novel ALK(F1174S) 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- Animals
- Base Sequence
- DNA Primers
- Disease Progression
- Gene Expression Profiling
- Humans
- Immunohistochemistry
- Infant
- Male
- Mice
- Mutation
- NIH 3T3 Cells
- Neuroblastoma
- genetics
- pathology
- therapy
- PC12 Cells
- Polymorphism
- Single Nucleotide
- Protein-Tyrosine Kinases
- genetics
- Rats
- Signal Transduction
- ALK
- Molecular biology
- molekylärbiologi
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Martinsson, Tomm ...
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Eriksson, Theres ...
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Abrahamsson, Jon ...
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Carén, Helena, 1 ...
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Hansson, Magnus
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Kogner, Per
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Kamaraj, Sattu
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Schönherr, Chris ...
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Weinmar, Joel
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Ruuth, Kristina
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Palmer, Ruth
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Hallberg, Bengt, ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
- Articles in the publication
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Cancer research
- By the university
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University of Gothenburg
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Karolinska Institutet
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Umeå University