Appearance of the novel activating F1174S ALK mutation in neuroblastoma correlates with aggressive tumor progression and unresponsiveness to therapy.
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.
Department of Clinical Genetics, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. tommy.martinsson@gu.se
Tommy
T
Martinsson
Therese
T
Eriksson
Jonas
J
Abrahamsson
Helena
H
Caren
Magnus
M
Hansson
Per
P
Kogner
Sattu
S
Kamaraj
Christina
C
Schönherr
Joel
J
Weinmar
Kristina
K
Ruuth
Ruth H
RH
Palmer
Bengt
B
Hallberg
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D018450:Disease Progression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D016716:PC12 Cells; D020641:Polymorphism, Single Nucleotide; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases; D015398:Signal Transduction
D017931:DNA Primers; C000626173:ALK protein, human; C000626174:Alk protein, mouse; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases