This study investigates the role of ALK gene mutations in neuroblastoma, a common and often fatal childhood cancer. The researchers identified five non-synonymous sequence variations in the kinase domain of the ALK gene, three of which were somatic and two were germline. The most frequent mutation, F1174L, was found in three different neuroblastoma cell lines. These mutations transformed IL-3-dependent murine hematopoietic Ba/F3 cells to cytokine-independent growth and were sensitive to the ALK inhibitor TAE684. In human neuroblastoma cell lines harboring the F1174L mutation, the inhibitor also induced apoptosis and impaired cell proliferation. The study demonstrates that activating mutations in the ALK receptor tyrosine kinase are present in primary neuroblastoma tumors and established neuroblastoma cell lines, providing a molecular rationale for targeted therapy with ALK inhibitors.This study investigates the role of ALK gene mutations in neuroblastoma, a common and often fatal childhood cancer. The researchers identified five non-synonymous sequence variations in the kinase domain of the ALK gene, three of which were somatic and two were germline. The most frequent mutation, F1174L, was found in three different neuroblastoma cell lines. These mutations transformed IL-3-dependent murine hematopoietic Ba/F3 cells to cytokine-independent growth and were sensitive to the ALK inhibitor TAE684. In human neuroblastoma cell lines harboring the F1174L mutation, the inhibitor also induced apoptosis and impaired cell proliferation. The study demonstrates that activating mutations in the ALK receptor tyrosine kinase are present in primary neuroblastoma tumors and established neuroblastoma cell lines, providing a molecular rationale for targeted therapy with ALK inhibitors.