title: Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumor.
abstract: Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal proliferation of transformed myofibroblasts, with a prominent inflammatory cell component, that can mimic other spindle cell processes such as nodular fasciitis, desmoid tumor, and gastrointestinal stromal tumor. Genetic analyses have recently demonstrated rearrangements of anaplastic lymphoma kinase (ALK), located at 2p23, in a subset of IMTs. Molecular characterizations have identified ALK fusions involving tropomyosin-3 and -4 (TPM-3 and -4), the clathrin heavy chain (CLTC), and the cysteinyl-tRNA synthetase (CARS) genes as fusion partners. Here we describe two IMTs with a novel ALK fusion that involves the Ran-binding protein 2 (RANBP2) gene at 2q13, which normally encodes a large (358-kDa) nucleopore protein localized at the cytoplasmic side of the nuclear pore complex. The N-terminal 867 residues of RANBP2 are fused to the cytoplasmic segment of ALK in the 1,430-amino acid RANBP2-ALK chimeric protein. Myofibroblasts that express RANBP2-ALK exhibit nuclear membrane-associated ALK staining that is unique compared to the subcellular localization observed with other ALK fusions in IMT, presumably attributable to heteroassociation of the fusion with normal RANBP2 at the nuclear pore. These findings expand the spectrum of ALK abnormalities observed in IMT and further confirm the clonal, neoplastic nature of these lesions.
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.
authors.forename: Zhigui
authors.initials: Z
authors.lastname: Ma
authors.forename: D Ashley
authors.initials: DA
authors.lastname: Hill
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Collins
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Morris
authors.forename: Janos
authors.initials: J
authors.lastname: Sumegi
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.forename: Craig
authors.initials: C
authors.lastname: Zuppan
authors.forename: Julia A
authors.initials: JA
authors.lastname: Bridge
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D000077548:Anaplastic Lymphoma Kinase; D001483:Base Sequence / Q000235:genetics; D002648:Child; D019457:Chromosome Breakage; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D020732:Cytogenetic Analysis / Q000379:methods; D005347:Fibroblasts / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007249:Inflammation / Q000235:genetics; D008297:Male; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D009379:Neoplasms, Muscle Tissue / Q000737:chemistry / Q000235:genetics*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics* / Q000276:immunology; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000276:immunology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics
chemical_list: D018832:Molecular Chaperones; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; C000591371:RANBP2-ALK fusion protein, human; C094493:ran-binding protein 2; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases