Reference Detail

Ref Type

Journal Article

PMID

(22705984)

Authors

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 KW, Yap SP, Lee KA, Lim LC, Tan D, Goh C, Cutcutache I, Yu W, Ng CC, Rajasegaran V, Heng HL, Gan A, Ong CK, Rozen S, Tan P, Teh BT, Lim ST

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	2	7	2012 Jul	591-7	Cancer Discov

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
JAK3	A572V	missense	gain of function	JAK3 A572V lies within protein kinase domain 1 of the Jak3 protein (UniProt.org). A572V confers a gain of function to the Jak3 protein, as demonstrated by increased Jak3 autophosphorylation (PMID: 29046866), constitutive phosphorylation of Jak3 and activation of downstream Stat5 (PMID: 22705984, PMID: 35622134), and leads to cytokine-independent proliferation of cultured cells (PMID: 22705984, PMID: 28284718).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
JAK3 A572V	mature T-cell and NK-cell lymphoma	sensitive	Tofacitinib	Preclinical	Actionable	In a preclinical study, Xeljanz (tofacitinib), a pan-JAK inhibitor, reduced cell viability and increased apoptosis in a JAK3 A572V mutant natural killer/T-cell lymphoma cell line (PMID: 22705984).	22705984