Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma

Cancer Discov. 2012 Jul;2(7):591-7. doi: 10.1158/2159-8290.CD-12-0028. Epub 2012 Jun 15.


The molecular pathogenesis of natural killer/T-cell lymphoma (NKTCL) is not well understood. We conducted whole-exome sequencing and identified Janus kinase 3 (JAK3) somatic-activating mutations (A572V and A573V) in 2 of 4 patients with NKTCLs. Further validation of the prevalence of JAK3 mutations was determined by Sanger sequencing and high-resolution melt (HRM) analysis in an additional 61 cases. In total, 23 of 65 (35.4%) cases harbored JAK3 mutations. Functional characterization of the JAK3 mutations support its involvement in cytokine-independent JAK/STAT constitutive activation leading to increased cell growth. Moreover, treatment of both JAK3-mutant and wild-type NKTCL cell lines with a novel pan-JAK inhibitor, CP-690550, resulted in dose-dependent reduction of phosphorylated STAT5, reduced cell viability, and increased apoptosis. Hence, targeting the deregulated JAK/STAT pathway could be a promising therapy for patients with NKTCLs.

Significance: Gene mutations causing NKTCL have not been fully identified. Through exome sequencing, we identified activating mutations of JAK3 that may play a significant role in the pathogenesis of NKTCLs. Our findings have important implications for the management of patients with NKTCLs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation
  • DNA Mutational Analysis
  • Enzyme Activation / genetics
  • Female
  • Humans
  • Janus Kinase 3 / antagonists & inhibitors
  • Janus Kinase 3 / genetics*
  • Janus Kinase 3 / metabolism
  • Lymphoma, T-Cell / genetics*
  • Lymphoma, T-Cell / metabolism
  • Lymphoma, T-Cell / pathology
  • Male
  • Middle Aged
  • Mutation*
  • Natural Killer T-Cells / metabolism*
  • Natural Killer T-Cells / pathology
  • Phosphorylation
  • Piperidines
  • Pyrimidines / pharmacology
  • Pyrroles / pharmacology
  • RNA Interference
  • STAT5 Transcription Factor / metabolism


  • Piperidines
  • Pyrimidines
  • Pyrroles
  • STAT5 Transcription Factor
  • tofacitinib
  • JAK3 protein, human
  • Janus Kinase 3