Janus Kinase 3 Activating Mutations Identified in Natural-Killer/T-Cell Lymphoma

The molecular pathogenesis of Natural-killer/T-cell lymphoma (NKTCL) is not well understood. We performed whole-exome sequencing and identified Janus kinase 3 (JAK3) somatic activating mutations (A572V and A573V) in two out of four NKTCL patients. 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-690,550, 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 NKTCL patients.