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(American Journal of Pathology. 2005;167:213-222.)
© 2005 American Society for Investigative Pathology

Biological Role of Anaplastic Lymphoma Kinase in Neuroblastoma

Yuko Osajima-Hakomori*¶||, Izumi Miyake*{dagger}, Miki Ohira{ddagger}, Akira Nakagawara{ddagger}, Atsuko Nakagawa§ and Ryuichi Sakai*

From the Growth Factor Division,* National Cancer Center Research Institute, Chuo-ku, Tokyo; St. Marianna University School of Medicine, Kawasaki-shi, Kanagawa; Tokyo Metropolitan Geriatric Hospital,|| Itabashi-ku, Tokyo; the Department of Pediatrics,{dagger} Kitasato University School of Medicine, Sagamihara-shi, Kanagawa; the Division of Biochemistry,{ddagger} Chiba Cancer Center Research Institute, Cyuo-ku, Chiba; and the Department of Pathology,§ Aichi Medical University, Aichi-gun, Aichi, Japan

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor originally identified as part of the chimeric nucleophosmin-ALK protein in the t(2;5) chromosomal rearrangement associated with anaplastic large cell lymphoma. We recently demonstrated that the ALK kinase is constitutively activated by gene amplification at the ALK locus in several neuroblastoma cell lines. Forming a stable complex with hyperphosphorylated ShcC, activated ALK modifies the responsiveness of the mitogen-activated protein kinase pathway to growth factors. In the present study, the biological role of activated ALK was examined by suppressing the expression of ALK kinase in neuroblastoma cell lines using an RNA interference technique. The suppression of activated ALK in neuroblastoma cells by RNA interference significantly reduced the phosphorylation of ShcC, mitogen-activated protein kinases, and Akt, inducing rapid apoptosis in the cells. By immunohistochemical analysis, the cytoplasmic expression of ALK was detected in most of the samples of neuroblastoma tissues regardless of the stage of the tumor, whereas significant amplification of ALK was observed in only 1 of 85 cases of human neuroblastoma samples. These data demonstrate the limited frequency of ALK activation in the real progression of neuroblastoma.




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