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Title: Janus kinase 3-activating mutations identifi ed in natural killer/T-cell lymphoma
Authors: Koo, G.C.
Tan, S.Y.
Tang, T.
Poon, S.L.
Allen, G.E.
Tan, L.
Chong, S.C.
Ong, W.S.
Tay, K.
Tao, M.
Quek, R.
Loong, S.
Yeoh, K.-W.
Yap, S.P.
Lee, K.A.
Lim, L.C.
Tan, D.
Goh, C.
Cutcutache, I. 
Yu, W.
Ng, C.C.Y.
Rajasegaran, V.
Heng, H.L.
Gan, A.
Ong, C.K.
Rozen, S. 
Tan, P. 
Teh, B.T.
Lim, S.T.
Issue Date: 2012
Citation: Koo, G.C., Tan, S.Y., Tang, T., Poon, S.L., Allen, G.E., Tan, L., Chong, S.C., Ong, W.S., Tay, K., Tao, M., Quek, R., Loong, S., Yeoh, K.-W., Yap, S.P., Lee, K.A., Lim, L.C., Tan, D., Goh, C., Cutcutache, I., Yu, W., Ng, C.C.Y., Rajasegaran, V., Heng, H.L., Gan, A., Ong, C.K., Rozen, S., Tan, P., Teh, B.T., Lim, S.T. (2012). Janus kinase 3-activating mutations identifi ed in natural killer/T-cell lymphoma. Cancer Discovery 2 (7) : 591-597. ScholarBank@NUS Repository.
Abstract: 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. © 2012 American Association for Cancer Research.
Source Title: Cancer Discovery
ISSN: 21598274
DOI: 10.1158/2159-8290.CD-12-0028
Appears in Collections:Staff Publications

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