title: A novel recurrent NPM1-TYK2 gene fusion in cutaneous CD30-positive lymphoproliferative disorders.
abstract: The spectrum of cutaneous CD30-positive lymphoproliferative disorders (LPDs) includes lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Chromosomal translocations targeting tyrosine kinases in CD30-positive LPDs have not been described. Using whole-transcriptome sequencing, we identified a chimeric fusion involving NPM1 (5q35) and TYK2 (19p13) that encodes an NPM1-TYK2 protein containing the oligomerization domain of NPM1 and an intact catalytic domain in TYK2. Fluorescence in situ hybridization revealed NPM1-TYK2 fusions in 2 of 47 (4%) primary cases of CD30-positive LPDs and was absent in other mature T-cell neoplasms (n = 151). Functionally, NPM1-TYK2 induced constitutive TYK2, signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activation. Conversely, a kinase-defective NPM1-TYK2 mutant abrogated STAT1/3/5 signaling. Finally, short hairpin RNA-mediated silencing of TYK2 abrogated lymphoma cell growth. This is the first report of recurrent translocations involving TYK2, and it highlights the novel therapeutic opportunities in the treatment of CD30-positive LPDs with TYK2 translocations.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
authors.forename: Thirunavukkarasu
authors.initials: T
authors.lastname: Velusamy
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kiel
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
authors.forename: Anagh A
authors.initials: AA
authors.lastname: Sahasrabuddhe
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
authors.forename: Delphine
authors.initials: D
authors.lastname: Rolland
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Dixon
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
authors.forename: Nathanael G
authors.initials: NG
authors.lastname: Bailey
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Betz
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
authors.forename: Noah A
authors.initials: NA
authors.lastname: Brown
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Hristov
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI;
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Wilcox
authors.affiliation: Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston TX;
authors.forename: Roberto N
authors.initials: RN
authors.lastname: Miranda
authors.affiliation: Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston TX;
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul, South Korea; and.
authors.forename: Yoon K
authors.initials: YK
authors.lastname: Jeon
authors.affiliation: Department of Pathology, Henry Ford Health System, Detroit, MI.
authors.forename: Kedar V
authors.initials: KV
authors.lastname: Inamdar
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
authors.forename: Megan S
authors.initials: MS
authors.lastname: Lim
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
authors.forename: Kojo S J
authors.initials: KS
authors.lastname: Elenitoba-Johnson
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D017730:Ki-1 Antigen / Q000235:genetics* / Q000378:metabolism; D054446:Lymphoma, Primary Cutaneous Anaplastic Large Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017731:Lymphomatoid Papulosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000090243:Nucleophosmin; D050596:Oncogene Fusion; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053634:TYK2 Kinase / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics
chemical_list: D017730:Ki-1 Antigen; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D000090243:Nucleophosmin; D053634:TYK2 Kinase; C070139:TYK2 protein, human