Neuroblastoma, an embryonal tumour of the peripheral sympathetic nervous system, 
accounts for approximately 15% of all deaths due to childhood cancer. High-risk 
neuroblastomas are rapidly progressive; even with intensive myeloablative 
chemotherapy, relapse is common and almost uniformly fatal. Here we report the 
detection of previously unknown mutations in the ALK gene, which encodes a 
receptor tyrosine kinase, in 8% of primary neuroblastomas. Five non-synonymous 
sequence variations were identified in the kinase domain of ALK, of which three 
were somatic and two were germ line. The most frequent mutation, F1174L, was 
also identified in three different neuroblastoma cell lines. ALK complementary 
DNAs encoding the F1174L and R1275Q variants, but not the wild-type ALK cDNA, 
transformed interleukin-3-dependent murine haematopoietic Ba/F3 cells to 
cytokine-independent growth. Ba/F3 cells expressing these mutations were 
sensitive to the small-molecule inhibitor of ALK, TAE684 (ref. 4). Furthermore, 
two human neuroblastoma cell lines harbouring the F1174L mutation were also 
sensitive to the inhibitor. Cytotoxicity was associated with increased amounts 
of apoptosis as measured by TdT-mediated dUTP nick end labelling (TUNEL). Short 
hairpin RNA (shRNA)-mediated knockdown of ALK expression in neuroblastoma cell 
lines with the F1174L mutation also resulted in apoptosis and impaired cell 
proliferation. Thus, activating alleles of the ALK receptor tyrosine kinase are 
present in primary neuroblastoma tumours and in established neuroblastoma cell 
lines, and confer sensitivity to ALK inhibition with small molecules, providing 
a molecular rationale for targeted therapy of this disease.