A novel recurrent NPM1-TYK2 gene fusion in cutaneous CD30-positive lymphoproliferative disorders

Thirunavukkarasu Velusamy; Mark J Kiel; Anagh A Sahasrabuddhe; Delphine Rolland; Catherine A Dixon; Nathanael G Bailey; Bryan L Betz; Noah A Brown; Alexandra C Hristov; Ryan A Wilcox; Roberto N Miranda; L Jeffrey Medeiros; Yoon K Jeon; Kedar V Inamdar; Megan S Lim; Kojo S J Elenitoba-Johnson

doi:10.1182/blood-2014-07-588434

A novel recurrent NPM1-TYK2 gene fusion in cutaneous CD30-positive lymphoproliferative disorders

Blood. 2014 Dec 11;124(25):3768-71. doi: 10.1182/blood-2014-07-588434. Epub 2014 Oct 27.

Authors

Thirunavukkarasu Velusamy¹, Mark J Kiel¹, Anagh A Sahasrabuddhe¹, Delphine Rolland¹, Catherine A Dixon¹, Nathanael G Bailey¹, Bryan L Betz¹, Noah A Brown¹, Alexandra C Hristov¹, Ryan A Wilcox², Roberto N Miranda³, L Jeffrey Medeiros³, Yoon K Jeon⁴, Kedar V Inamdar⁵, Megan S Lim¹, Kojo S J Elenitoba-Johnson¹

Affiliations

¹ Department of Pathology, University of Michigan Medical School, Ann Arbor, MI;
² Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI;
³ Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston TX;
⁴ Department of Pathology, Seoul National University Hospital, Seoul, South Korea; and.
⁵ Department of Pathology, Henry Ford Health System, Detroit, MI.

PMID: 25349176
DOI: 10.1182/blood-2014-07-588434

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.

MeSH terms

Blotting, Western
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
HEK293 Cells
Humans
In Situ Hybridization, Fluorescence
Ki-1 Antigen / genetics*
Ki-1 Antigen / metabolism
Lymphoma, Primary Cutaneous Anaplastic Large Cell / genetics*
Lymphoma, Primary Cutaneous Anaplastic Large Cell / metabolism
Lymphoma, Primary Cutaneous Anaplastic Large Cell / pathology
Lymphomatoid Papulosis / genetics*
Lymphomatoid Papulosis / metabolism
Lymphomatoid Papulosis / pathology
Mutation
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Nucleophosmin
Oncogene Fusion
Oncogene Proteins, Fusion / genetics*
Oncogene Proteins, Fusion / metabolism
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
STAT1 Transcription Factor / genetics
STAT1 Transcription Factor / metabolism
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / metabolism
STAT5 Transcription Factor / genetics
STAT5 Transcription Factor / metabolism
Signal Transduction / genetics
Skin Neoplasms / genetics*
Skin Neoplasms / metabolism
Skin Neoplasms / pathology
TYK2 Kinase / genetics*
TYK2 Kinase / metabolism
Transcriptome / genetics

Substances

Ki-1 Antigen
NPM1 protein, human
Nuclear Proteins
Oncogene Proteins, Fusion
STAT1 Transcription Factor
STAT3 Transcription Factor
STAT5 Transcription Factor
Nucleophosmin
TYK2 Kinase
TYK2 protein, human