Fusion of a Kinase Gene, ALK , to a Nucleolar Protein Gene, NPM , in Non-Hodgkin's Lymphoma

Abstract

The 2;5 chromosomal translocation occurs in most anaplastic large-cell non-Hodgkin's lymphomas arising from activated T lymphocytes. This rearrangement was shown to fuse the NPM nucleolar phosphoprotein gene on chromosome 5q35 to a previously unidentified protein tyrosine kinase gene, ALK, on chromosome 2p23. In the predicted hybrid protein, the amino terminus of nucleophosmin (NPM) is linked to the catalytic domain of anaplastic lymphoma kinase (ALK). Expressed in the small intestine, testis, and brain but not in normal lymphoid cells, ALK shows greatest sequence similarity to the insulin receptor subfamily of kinases. Unscheduled expression of the truncated ALK may contribute to malignant transformation in these lymphomas.

Renal cell carcinoma with novel VCL–ALK fusion: new representative of ALK-associated tumor spectrum

“…The ALK gene rearrangement was originally discovered in anaplastic large cell lymphoma, and the NPM1 gene was its most common translocation partner. 11 Subsequently, recurrent ALK chimeric oncogenes involving diverse partner genes (RanBP2, CLTC, CARS, and others) were identified in inflammatory myofibroblastic tumors. [15][16][17][18] More recently, the ALK gene has been shown to be involved in small subsets of epithelial malignancies, including carcinomas of pulmonary, esophageal, mammary gland, and gastrointestinal origin.…”

“…11 Subsequently, ALK rearrangements were found in several phenotypically different hematologic neoplasms [12][13][14] and in histogenetically unrelated inflammatory myofibroblastic tumor. [15][16][17][18] Recently, ALK rearrangements and EML4-ALK and KIF5B-ALK fusions were discovered in a subset of non-small cell lung carcinomas; 19,20 proteomics reports suggested a possible TPM4-ALK fusion in esophageal carcinoma; 21,22 and an exon array profiling study demonstrated the EML4-ALK fusion in 2.5% of breast and colon cancers.…”

Dependence receptors: a new paradigm in cell signaling and cancer therapy

“…It was initially identified as part of the oncogenic nucleophosmin-ALK fusion protein resulting from the t(2;5) translocation that is frequently associated with anaplastic large-cell lymphoma (Morris et al, 1994). Nucleophosmin allows dimerization of the fusion protein, causing constitutive activation of ALK kinase and downstream activation of phospholipase C-g, PI3K, STATs and pp60c-src (Allouche, 2007).…”

Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA

“…T-cell lymphomas (TCLs) that express the kinase represent a prototypic ALK-driven malignancy (Chiarle et al, 2008;Li and Morris, 2008). The expression of ALK results in the affected CD4 þ T lymphocytes from translocations involving the ALK gene and several different partners, by far the most frequently, the nucleophosmin (NPM) gene (Morris et al, 1994;Shiota et al, 1994). The NPM/ ALK chimeric protein is constitutively expressed and activated through autophosphorylation (Shiota et al, 1994;Morris et al, 1997).…”