title: ALK-positive diffuse large B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of 6 cases.
abstract: Expression of ALK protein by lymphoid cells and the description of variant anaplastic lymphoma kinase (ALK) translocations have typically been restricted to cases of T-cell and null anaplastic large-cell lymphoma (ALCL). All such cases result from a novel fusion created by the ALK gene on chromosome 2p23 and NPM on 5q35 or other variant translocation partners. A rare variant of diffuse large B-cell lymphoma (DLBCL), originally described in 1997, was thought to overexpress full-length ALK in contrast to a chimeric protein characteristic of ALCL. However, full-length ALK protein lacks tyrosine kinase activity and thus the mechanism of oncogenesis has remained elusive. We describe 6 cases of ALK+ DLBCL characterized by a simple or complex t(2;17)(p23;q23) involving the clathrin gene (CLTC) at chromosome band 17q23 and the ALK gene at chromosome band 2p23. All cases were studied using fluorescence in situ hybridization (FISH), complemented in one case with standard cytogenetic analysis, multicolor karyotyping (M-FISH), and reverse transcriptase-polymerase chain reaction. These results clearly demonstrate that most cases of ALK+ DLBCL share the same mechanism of deregulated ALK expression. Moreover, these results demonstrate the presence of CLTC-ALK fusions in these tumors and extend the list of diseases associated with this genetic abnormality to include classical T-cell or null ALCL, ALK+ DLBCL, and inflammatory myofibroblastic tumors.
authors.affiliation: Department of Oncogeneiss and Signaling in Hematopoietic Cells, Instiut National de la Santé et de la Recherche Médicale U-563, Centre de Physiopatholgie de Toulouse-Purpan, France.
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.forename: Laurence
authors.initials: L
authors.lastname: Lamant
authors.forename: Jose I
authors.initials: JI
authors.lastname: Martin-Subero
authors.forename: Valia S
authors.initials: VS
authors.lastname: Lestou
authors.forename: Nancy Lee
authors.initials: NL
authors.lastname: Harris
authors.forename: Hans-Konrad
authors.initials: HK
authors.lastname: Müller-Hermelink
authors.forename: John F
authors.initials: JF
authors.lastname: Seymour
authors.forename: Lynda J
authors.initials: LJ
authors.lastname: Campbell
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Horsman
authors.forename: Isabelle
authors.initials: I
authors.lastname: Auvigne
authors.forename: Estelle
authors.initials: E
authors.lastname: Espinos
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.forename: Georges
authors.initials: G
authors.lastname: Delsol
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D002966:Clathrin / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement / Q000235:genetics*; D006801:Humans; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D002966:Clathrin; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; C408996:oncoprotein CLTCL-ALK; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases