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A New Variant Anaplastic Lymphoma Kinase (ALK)-Fusion Protein (ATIC-ALK) in a Case of ALK-positive Anaplastic Large Cell Lymphoma¹

Department of Experimental Oncology, Istituto Europeo di Oncologia, 20141 Milan, Italy [M. T., L. L., P-G. P.]; Department of Pathology, University of Barcelona, Barcelona, Spain [E. C.]; LRF Immunodiagnostics Unit, John Radcliffe Hospital, Oxford, United Kingdom [K. P., D. Y. M.]; and Institute of Hematology, University of Perugia, 06100 Perugia, Italy [B. F.]

Anaplastic lymphoma kinase (ALK)-positive lymphomas ("ALKomas") constitute a distinct molecular and clinicopathological entity within the heterogeneous group of CD30-positive large cell lymphomas. In 80–85% of cases tumor cells express a M_r 80,000 hybrid protein comprising the nucleolar phosphoprotein nucleophosmin (NPM) and the ALK. We report here the cloning and expression of a novel ALK-fusion protein from an ALK-positive lymphoma. This case was selected for molecular investigation because of (a) the absence of NPM-ALK transcripts; (b) the atypical staining patterns for ALK (cytoplasm-restricted) and for NPM (nucleus-restricted); and (c) the presence of a M_r 96,000 ALK-protein differing in size from NPM-ALK. Nucleotide sequence analysis of ALK transcripts isolated by 5'-rapid amplification of cDNA ends revealed a chimeric mRNA corresponding to an ATIC-ALK in-frame fusion. ATIC is a bifunctional enzyme (5-aminoimidazole-4-carboxamide ribonucleotide transformylase and IMP cyclohydrolase enzymatic activities) that catalyzes the penultimate and final enzymatic activities of the purine nucleotide synthesis pathway. Expression of full-length ATIC-ALK cDNA in mouse fibroblasts revealed that the fusion protein (a) possesses constitutive tyrosine kinase activity; (b) forms stable complexes with the signaling proteins Grb2 and Shc; (c) induces tyrosine-phosphorylation of Shc; and (d) provokes oncogenic transformation. These findings point to fusion with ATIC as an alternative mechanism of ALK activation.

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