Related Experiment Video
Updated: Mar 6, 2026
Flow Cytometry-based Assay for the Monitoring of NK Cell Functions
Published on: October 30, 2016
Novel JAK3-Activating Mutations in Extranodal NK/T-Cell Lymphoma, Nasal Type
Sung Hoon Sim1, Soyeon Kim2, Tae Min Kim1
1Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
Abstract:
Inhibition of the Janus kinase (JAK)-STAT pathway has been implicated as a treatment option for extranodal natural killer/T-cell lymphoma, nasal type (NTCL). However, JAK-STAT pathway alterations in NTCL are variable, and the efficacy of JAK-STAT pathway inhibition has been poorly evaluated. JAK3 mutation and STAT3 genetic alterations were investigated by direct sequencing and immunohistochemistry in 84 patients with newly diagnosed NTCL. Five of 71 patients with NTCL (7.0%) had JAK3 mutations in the pseudokinase domain: two JAK3A573V, two JAK3H583Y, and one JAK3G589D mutation. Proliferation of Ba/F3 cells transduced with novel JAK3 mutations (JAK3H583Y and JAK3G589D) was independent of IL-3 and was inhibited by the JAK3 inhibitor tofacitinib (means ± SD drug concentration causing a 50% inhibition of the desired activity, 85 ± 10 nmol/L and 54 ± 9 nmol/L). Ribbon diagrams revealed that these JAK3 pseudokinase domain mutations were located at the pseudokinase-kinase domain interface. Although phosphorylated STAT3 was overexpressed in 35 of 68 patients with NTCL (51.4%), a STAT3 mutation (p.Tyr640Phe; STAT3Y640F) at the SRC homology 2 domain was detected in 1 of the 63 patients (1.5%). A STAT3 inhibitor was active against STAT3-mutant SNK-6 and YT cells. Novel JAK3 mutations are oncogenic and druggable in NTCL. The JAK3 or STAT3 signal was altered in NTCL, and pathway inhibition might be a therapeutic option for patients with JAK3- or STAT3-mutant NTCL.
Insights
Novel Janus kinase (JAK)-STAT pathway mutations were identified in extranodal natural killer/T-cell lymphoma (NTCL). These JAK3 and STAT3 alterations are oncogenic and may represent therapeutic targets for NTCL treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The Janus kinase (JAK)-STAT pathway is a potential therapeutic target for extranodal natural killer/T-cell lymphoma (NTCL).
- However, alterations in this pathway within NTCL are diverse, and the effectiveness of targeting it requires further investigation.
Purpose of the Study:
- To investigate JAK3 mutations and STAT3 genetic alterations in patients with newly diagnosed NTCL.
- To evaluate the oncogenic potential and druggability of novel JAK3 mutations.
- To assess the therapeutic implications of JAK-STAT pathway alterations in NTCL.
Main Methods:
- Direct sequencing and immunohistochemistry were employed to analyze JAK3 and STAT3 in 84 NTCL patients.
- Functional assays were performed using Ba/F3 cells to assess the proliferation of cells with novel JAK3 mutations.
- Ribbon diagrams were used to visualize the location of JAK3 mutations within the protein structure.
Main Results:
- Seven percent of NTCL patients (5/71) harbored JAK3 mutations (JAK3A573V, JAK3H583Y, JAK3G589D) in the pseudokinase domain.
- Novel JAK3 mutations (JAK3H583Y, JAK3G589D) conferred IL-3 independent proliferation, sensitive to the JAK3 inhibitor tofacitinib.
- Overexpression of phosphorylated STAT3 was observed in 51.4% of patients, while a STAT3 mutation (STAT3Y640F) was found in 1.5% of patients.
Conclusions:
- Novel JAK3 mutations identified in NTCL are oncogenic and susceptible to targeted inhibition.
- Alterations in the JAK3 or STAT3 signaling pathway are present in NTCL.
- Targeting the JAK-STAT pathway may offer a viable therapeutic strategy for NTCL patients with specific JAK3 or STAT3 mutations.
