Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large‐cell lymphoma and inflammatory myofibroblastic tumor

ALK‐positive anaplastic large‐cell lymphoma (ALCL) has been recognized as a distinct type of lymphoma in the heterogeneous group of T/Null‐ALCL. While most of the ALK‐positive ALCL (ALKomas) are characterized by the presence of the NPM‐ALK fusion protein, the product of the t(2;5)(p23;q35), 10–20% of ALKomas contain variant ALK fusions, including ATIC‐ALK, TFG‐ALK, CLTC‐ALK (previously designated CLTCL‐ALK), TMP3‐ALK, and MSN‐ALK. TMP3‐ALK and TMP4‐ALK fusions also have been detected in inflammatory myofibroblastic tumors (IMTs), making clear that aberrations of the ALK gene are not associated exclusively with the pathogenesis of ALK‐positive ALCL. Here we report results of molecular studies on two lymphoma cases and one IMT case with variant rearrangements of ALK. Our study led to the detection of the CLTC‐ALK fusion in an ALCL case and to the identification of two novel fusion partners of ALK: ALO17 (KIAA1618), a gene with unknown function, which was fused to ALK in an ALCL case with a t(2;17)(p23;q25), and CARS, encoding the cysteinyl‐tRNA synthetase, which was fused to ALK in an IMT case with a t(2;11;2)(p23;p15;q31). These results confirm the recurrent involvement of ALK in IMT and further demonstrate the diversity of ALK fusion partners, with the ability to homodimerize as a common characteristic. © 2002 Wiley‐Liss, Inc.

[1]  M. Ladanyi,et al.  Fusion of the ALK gene to the clathrin heavy chain gene, CLTC, in inflammatory myofibroblastic tumor. , 2001, The American journal of pathology.

[2]  M. Shimizu,et al.  Anaplastic Lymphoma Kinase Expression in Inflammatory Pseudotumors , 2001, The American journal of surgical pathology.

[3]  P. Marynen,et al.  The NPM-ALK and the ATIC-ALK fusion genes can be detected in non-neoplastic cells. , 2001, The American journal of pathology.

[4]  S. Perkins,et al.  ALK1 and p80 Expression and Chromosomal Rearrangements Involving 2p23 in Inflammatory Myofibroblastic Tumor , 2001, Modern Pathology.

[5]  D. Wen,et al.  Identification of Anaplastic Lymphoma Kinase as a Receptor for the Growth Factor Pleiotrophin* , 2001, The Journal of Biological Chemistry.

[6]  S. Morris,et al.  Alk+ CD30+ lymphomas: a distinct molecular genetic subtype of non‐hodgkin's lymphoma , 2001, British journal of haematology.

[7]  J. Coindre,et al.  ALK probe rearrangement in a t(2;11;2)(p23;p15;q31) translocation found in a prenatal myofibroblastic fibrous lesion: Toward a molecular definition of an inflammatory myofibroblastic tumor family? , 2001, Genes, chromosomes & cancer.

[8]  E. Campo,et al.  Molecular Characterization of a New ALK Translocation Involving Moesin (MSN-ALK) in Anaplastic Large Cell Lymphoma , 2001, Laboratory Investigation.

[9]  S. Pileri,et al.  CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. , 2000, Blood.

[10]  P. D. Dal Cin,et al.  TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. , 2000, The American journal of pathology.

[11]  K. Pulford,et al.  Further demonstration of the diversity of chromosomal changes involving 2p23 in ALK-positive lymphoma: 2 cases expressing ALK kinase fused to CLTCL (clathrin chain polypeptide-like). , 2000, Blood.

[12]  R. Siebert,et al.  Inv(2)(p23q35) in anaplastic large-cell lymphoma induces constitutive anaplastic lymphoma kinase (ALK) tyrosine kinase activation by fusion to ATIC, an enzyme involved in purine nucleotide biosynthesis. , 2000, Blood.

[13]  A. Rosenwald,et al.  TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations. , 1999, Blood.

[14]  C. Griffin,et al.  Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. , 1999, Cancer research.

[15]  R. Fletterick,et al.  Clathrin self-assembly is mediated by a tandemly repeated superhelix , 1999, Nature.

[16]  K. Pulford,et al.  A new fusion gene TPM3-ALK in anaplastic large cell lymphoma created by a (1;2)(q25;p23) translocation. , 1999, Blood.

[17]  S. Pileri,et al.  ALK+ lymphoma: clinico-pathological findings and outcome. , 1999, Blood.

[18]  A. Hagemeijer,et al.  The cryptic inv(2)(p23q35) defines a new molecular genetic subtype of ALK-positive anaplastic large-cell lymphoma. , 1998, Blood.

[19]  S. Pileri,et al.  ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum. , 1998, The American journal of pathology.

[20]  J. L. Le Caer,et al.  Cysteinyl-tRNA synthetase from Saccharomyces cerevisiae. Purification, characterization and assignment to the genomic sequence YNL247w. , 1997, Biochimie.

[21]  M. Seto,et al.  Anaplastic large cell lymphoma: a distinct molecular pathologic entity: a reappraisal with special reference to p80(NPM/ALK) expression. , 1997, The American journal of surgical pathology.

[22]  A. Feinberg,et al.  A 2.5-Mb transcript map of a tumor-suppressing subchromosomal transferable fragment from 11p15.5, and isolation and sequence analysis of three novel genes. , 1997, Genomics.

[23]  E. Campo,et al.  The monoclonal antibody ALK1 identifies a distinct morphological subtype of anaplastic large cell lymphoma associated with 2p23/ALK rearrangements. , 1997, The American journal of pathology.

[24]  C. Naeve,et al.  ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK) , 1997, Oncogene.

[25]  K. Pulford,et al.  Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis , 1997, Molecular and cellular biology.

[26]  D. Weisenburger,et al.  Detection of the t(2;5)(p23;q35) and NPM-ALK fusion in non-Hodgkin's lymphoma by two-color fluorescence in situ hybridization. , 1997, Blood.

[27]  K. Pulford,et al.  Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1. , 1997, Blood.

[28]  C. Mecucci,et al.  Successful use of the same slide for consecutive fluorescence in situ hybridization experiments , 1996, Genes, chromosomes & cancer.

[29]  H. Satoh,et al.  Diagnosis of t(2;5)(p23;q35)-associated Ki-1 lymphoma with immunohistochemistry. , 1994, Blood.

[30]  H Stein,et al.  A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. , 1994, Blood.

[31]  D N Shapiro,et al.  Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. , 1994, Science.

[32]  S. Arfin,et al.  Assignment of the cysteinyl-tRNA synthetase gene (CARS) to 11p15.5. , 1993, Genomics.

[33]  I. Kovalszky,et al.  Human clathrin heavy chain (CLTC): partial molecular cloning, expression, and mapping of the gene to human chromosome 17q11-qter. , 1991, Genomics.

[34]  K. Lennert,et al.  The expression of the Hodgkin's disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. , 1985, Blood.

[35]  J. Dignam,et al.  Purification and structural characterization of rat liver threonyl transfer ribonucleic acid synthetase. , 1980, Biochemistry.

[36]  T. Nagase,et al.  Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. , 2000, DNA research : an international journal for rapid publication of reports on genes and genomes.

[37]  Osamu Ohara,et al.  HUGE: a database for human large proteins identified by Kazusa cDNA sequencing project , 1999, Nucleic Acids Res..

[38]  A. Bernheim,et al.  High incidence of the t(2;5)(p23;q35) translocation in anaplastic large cell lymphoma and its lack of detection in Hodgkin's disease. Comparison of cytogenetic analysis, reverse transcriptase-polymerase chain reaction, and P-80 immunostaining. , 1996, Blood.

[39]  N. Nomura,et al.  Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain. , 1996, DNA research : an international journal for rapid publication of reports on genes and genomes.

[40]  S. Arfin,et al.  Nucleotide and deduced amino acid sequence of human cysteinyl-tRNA synthetase. , 1994, DNA sequence : the journal of DNA sequencing and mapping.