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Appearance of the novel activating F1174S ALK mutation in neuroblastoma correlates with aggressive tumour progression and unresponsiveness to therapy
Clinical Genetics, University of Gothenburg.
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Pediatrics, University of Gothenburg.
Clinical Genetics, University of Gothenburg.
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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
Abstract [en]

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.
Keyword [en]
ALK, neuroblastoma, gain of function
National Category
Cell and Molecular Biology
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-36978DOI: 10.1158/0008-5472.CAN-10-2366OAI: oai:DiVA.org:umu-36978DiVA: diva2:356944
Projects
Exploiting Drosophila as a model system for studying Anaplastic Lymphoma Kinase in vivo
Available from: 2010-10-14 Created: 2010-10-14 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Exploiting Drosophila as a model system for studying anaplastic lymphoma kinase in vivo
Open this publication in new window or tab >>Exploiting Drosophila as a model system for studying anaplastic lymphoma kinase in vivo
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Anaplastic Lymphoma Kinase (ALK) is a Receptor Tyrosine Kinase (RTK) and an oncogene associated with several human diseases, but its normal function in humans and other vertebrates is unclear. Drosophila melanogaster has an ALK homolog, demonstrating that the RTK has been conserved throughout evolution. This makes Drosophila a suitable model organism for studying not only Drosophila ALK function, but also to study mammalian forms of ALK. In Drosophila the ligand Jeb activates ALK, initiating signaling crucial for visceral mesoderm development. The activating ligand for mammalian ALK is unclear, and for this reason Drosophila was employed in a cross-species approach to investigate whether Drosophila Jeb can activate mouse ALK. Jeb is unable to activate mouse ALK, and therefore mouse ALK is unable to substitute for and rescue the Drosophila ALK mutant phenotype. This suggests that there has been significant evolution in the ALK-ligand relationship between the mouse and Drosophila.

In humans ALK has recently been shown to be involved in the development of neuroblastoma, a cancer tumor in children. I have developed a Drosophila model for examining human gain of function ALK mutants found in neuroblastoma patients. The various ALK variants have acquired point mutations in the kinase domain that have been predicted to activate the RTK in a constitutive and ligand independent manner. When expressed in the fly eye, active human ALK mutants result in a rough eye phenotype, while inactive wild type ALK does not, due to the lack of an activating ligand in the fly. In this way  several of the ALK mutations identified in neuroblastoma patients could be confirmed to be activated in a ligand independent manner. Moreover, a novel ALK mutant; ALKF1174S, was discovered in a neuroblastoma patient and was in the Drosophila model shown to be a gain of function mutation, and a previously predicted gain of function mutation; ALKI1250T, was shown to be a kinase dead mutation. This fly model can also be used for testing ALK selective inhibitors, for identifying activating ligands for human ALK and for identifying conserved components of the ALK signaling pathway.

Gut musculature development in Drosophila is dependent on ALK signaling, while somatic muscle development is not. Proteins of the Wasp-Scar signaling network regulate Arp2/3-complex mediated actin polymerization, and I have investigated their function in visceral and somatic muscle fusion. I found that Verprolin and other members of this protein family are essential for somatic but not visceral muscle development. Despite fusion defects in both tissues in Verprolin and other examined mutants, gut development proceeds, suggesting that fusion is not crucial for visceral mesoderm development. Hence the actin polymerization machinery functions in both somatic and visceral muscle fusion, but this process only appears to be essential in somatic muscle development.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2010. 58 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1376
Keyword
Anaplastic lymphoma kinase, Receptor tyrosine kinase, Jeb, neuroblastoma, actin polymerization, Wasp, Scar, Vrp1, Arp2/3
National Category
Cell and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-36991 (URN)978-91-7459-090-6 (ISBN)
Public defence
2010-11-05, Major Groove, Byggnad 6L, Umeå universitet, Umeå, 09:00 (English)
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Projects
Exploiting Drosophila as a model system for studying Anaplastic Lymphoma Kinase in vivo
Available from: 2010-10-15 Created: 2010-10-14 Last updated: 2010-10-15Bibliographically approved

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Eriksson, ThereseHansson, MagnusKamaraj, SattuSchönherr, ChristinaWeinmar, JoelRuuth, KristinaPalmer, RuthHallberg, Bengt

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Eriksson, ThereseHansson, MagnusKamaraj, SattuSchönherr, ChristinaWeinmar, JoelRuuth, KristinaPalmer, RuthHallberg, Bengt
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