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Cell culture and Drosophila model systems define three classes of anaplastic lymphoma kinase mutations in neuroblastoma.

Artikel i vetenskaplig tidskrift
Författare Damini Chand
Yasuo Yamazaki
Kristina Ruuth
Christina Schönherr
Tommy Martinsson
Per Kogner
Edward F Attiyeh
John Maris
Olena Morozova
Marco A Marra
Miki Ohira
Akira Nakagawara
Per-Erik Sandström
Ruth Palmer
Bengt Hallberg
Publicerad i Disease models & mechanisms
Volym 6
Nummer/häfte 2
Sidor 373-82
ISSN 1754-8411
Publiceringsår 2013
Publicerad vid Institutionen för biomedicin, avdelningen för medicinsk genetik och klinisk genetik
Sidor 373-82
Språk en
Länkar dx.doi.org/10.1242/dmm.010348
Ämneskategorier Medicinska grundvetenskaper

Sammanfattning

Neuroblastoma is a childhood extracranial solid tumor which is associated with a number of genetic changes. Included in these genetic alterations are mutations in the kinase domain of the Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase (RTK), which have been found in both somatic and familial neuroblastoma. In order to treat patients accordingly required characterisation of these mutations in terms of their response to ALK tyrosine kinase inhibitors (TKIs). Here, we report the identification and characterisation of two novel neuroblastoma ALK mutations (A1099T and 1464STOP) which we have investigated together with several previously reported but uncharacterised ALK mutations (T1087I, D1091N, T1151M, M1166R, F1174I and A1234T). In order to understand the potential role of these ALK mutations in neuroblastoma progression we have employed cell culture based systems together with the model organism Drosophila as a readout for ligand-independent activity. Mutation of ALK at position F1174I generates a gain-of-function receptor capable of activating intracellular targets, such as ERK (extracellular signal regulated kinase) and STAT3 (signal transducer and activator of transcription 3) in a ligand independent manner. Analysis of these previously uncharacterised ALK mutants and comparison with ALK(F1174) mutants suggests that ALK mutations observed in neuroblastoma fall into three classes. These are: (i) gain-of-function ligand independent mutations such as ALK(F1174), (ii) kinase-dead ALK mutants, e.g. ALK(I1250T)(Schonherr et al 2011a) or (iii) ALK mutations which are ligand-dependent in nature. Irrespective of the nature of the observed ALK mutants, in every case the activity of the mutant ALK receptors could be abrogated by the ALK inhibitor crizotinib (PF-02341066, Xalkori), albeit with differing levels of sensitivity.

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