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

• Published in: Cancer discovery 2012-07, Vol.2 (7), p.591-597
• Main Authors: Koo, Ghee Chong, Tan, Soo Yong, Tang, Tiffany, Poon, Song Ling, Allen, George E, Tan, Leonard, Chong, Soo Ching, Ong, Whee Sze, Tay, Kevin, Tao, Miriam, Quek, Richard, Loong, Susan, Yeoh, Kheng-Wei, Yap, Swee Peng, Lee, Kuo Ann, Lim, Lay Cheng, Tan, Daryl, Goh, Christopher, Cutcutache, Ioana, Yu, Willie, Ng, Cedric Chuan Young, Rajasegaran, Vikneswari, Heng, Hong Lee, Gan, Anna, Ong, Choon Kiat, Rozen, Steve, Tan, Patrick, Teh, Bin Tean, Lim, Soon Thye
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.CD-12-0028

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. 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.