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21598290cd120028-sup-t2_110k.pdf (110.81 kB)

Supplementary Table 2 from Janus Kinase 3–Activating Mutations Identified in Natural Killer/T-cell Lymphoma

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posted on 2023-04-03, 20:23 authored by Ghee Chong Koo, Soo Yong Tan, Tiffany Tang, Song Ling Poon, George E. Allen, Leonard Tan, Soo Ching Chong, Whee Sze Ong, Kevin Tay, Miriam Tao, Richard Quek, Susan Loong, Kheng-Wei Yeoh, Swee Peng Yap, Kuo Ann Lee, Lay Cheng Lim, Daryl Tan, Christopher Goh, Ioana Cutcutache, Willie Yu, Cedric Chuan Young Ng, Vikneswari Rajasegaran, Hong Lee Heng, Anna Gan, Choon Kiat Ong, Steve Rozen, Patrick Tan, Bin Tean Teh, Soon Thye Lim

PDF file - 110K, Non-synonymous somatic mutations identified in the Discovery set of four NKTCL cases

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ARTICLE ABSTRACT

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. Cancer Discov; 2(7); 591–7. ©2012 AACR.This article is highlighted in the In This Issue feature, p. 569.

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