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


CONCLUSIONS
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.
NCCS-VARI Translational Research Laboratory, Department of Medical Sciences, National Cancer Centre Singapore, Singapore.
Ghee Chong
GC
Koo
Soo Yong
SY
Tan
Tiffany
T
Tang
Song Ling
SL
Poon
George E
GE
Allen
Leonard
L
Tan
Soo Ching
SC
Chong
Whee Sze
WS
Ong
Kevin
K
Tay
Miriam
M
Tao
Richard
R
Quek
Susan
S
Loong
Kheng-Wei
KW
Yeoh
Swee Peng
SP
Yap
Kuo Ann
KA
Lee
Lay Cheng
LC
Lim
Daryl
D
Tan
Christopher
C
Goh
Ioana
I
Cutcutache
Willie
W
Yu
Cedric Chuan Young
CC
Ng
Vikneswari
V
Rajasegaran
Hong Lee
HL
Heng
Anna
A
Gan
Choon Kiat
CK
Ong
Steve
S
Rozen
Patrick
P
Tan
Bin Tean
BT
Teh
Soon Thye
ST
Lim
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004252:DNA Mutational Analysis; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D006801:Humans; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D055611:Natural Killer T-Cells / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D010880:Piperidines; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D034622:RNA Interference; D050799:STAT5 Transcription Factor / Q000378:metabolism
D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D050799:STAT5 Transcription Factor; C479163:tofacitinib; C507933:JAK3 protein, human; D053616:Janus Kinase 3