Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma.
UNLABELLED: 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.
Koo, GC; Tan, SY; Tang, T; Poon, SL; Allen, GE; Tan, L; Chong, SC; Ong, WS; Tay, K; Tao, M; Quek, R; Loong, S; Yeoh, K-W; Yap, SP; Lee, KA; Lim, LC; Tan, D; Goh, C; Cutcutache, I; Yu, W; Ng, CCY; Rajasegaran, V; Heng, HL; Gan, A; Ong, CK; Rozen, S; Tan, P; Teh, BT; Lim, ST
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