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

Publication ,  Journal Article
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 ...
Published in: Cancer Discov
July 2012

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.

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Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

July 2012

Volume

2

Issue

7

Start / End Page

591 / 597

Location

United States

Related Subject Headings

  • STAT5 Transcription Factor
  • RNA Interference
  • Pyrroles
  • Pyrimidines
  • Piperidines
  • Phosphorylation
  • Natural Killer T-Cells
  • Mutation
  • Middle Aged
  • Male
 

Citation

APA
Chicago
ICMJE
MLA
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Koo, G. C., Tan, S. Y., Tang, T., Poon, S. L., Allen, G. E., Tan, L., … Lim, S. T. (2012). Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma. Cancer Discov, 2(7), 591–597. https://doi.org/10.1158/2159-8290.CD-12-0028
Koo, Ghee Chong, Soo Yong Tan, Tiffany Tang, Song Ling Poon, George E. Allen, Leonard Tan, Soo Ching Chong, et al. “Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma.Cancer Discov 2, no. 7 (July 2012): 591–97. https://doi.org/10.1158/2159-8290.CD-12-0028.
Koo GC, Tan SY, Tang T, Poon SL, Allen GE, Tan L, et al. Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma. Cancer Discov. 2012 Jul;2(7):591–7.
Koo, Ghee Chong, et al. “Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma.Cancer Discov, vol. 2, no. 7, July 2012, pp. 591–97. Pubmed, doi:10.1158/2159-8290.CD-12-0028.
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. Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma. Cancer Discov. 2012 Jul;2(7):591–597.

Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

July 2012

Volume

2

Issue

7

Start / End Page

591 / 597

Location

United States

Related Subject Headings

  • STAT5 Transcription Factor
  • RNA Interference
  • Pyrroles
  • Pyrimidines
  • Piperidines
  • Phosphorylation
  • Natural Killer T-Cells
  • Mutation
  • Middle Aged
  • Male