Interim analysis after 2 to 3 cycles showed complete remission rate of 56%, partial remission rate of 22%, giving an overall response rate of 78%. On treatment completion, the overall-response rate became 81% (complete remission ‫؍‬ 66%, partial remission ‫؍‬ 15%). Response rates were similar for newly diagnosed or relapsed/refractory patients. At a median follow-up of 31 months (1-84 months), the 5-year overall survival was 50% and 4-year disease-free-survival was 64%. Multivariate analysis showed that international prognostic index was the most significant factor impacting on outcome and survivals. (Blood. 2012;120(15):2973-2980)

The molecular pathogenesis of natural killer/T-cell lymphoma (NKTCL) is not well understood. We conducted whole-exome sequencing and identifi ed 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 identifi ed. Through exome sequencing, we identifi ed activating mutations of JAK3 that may play a signifi cant role in the pathogenesis of NKTCLs. Our fi ndings have important implications for the management of patients with NKTCLs.Cancer Discov; 2(7); 591-7.