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Ref Type Journal Article
PMID (28284718)
Authors Sim SH, Kim S, Kim TM, Jeon YK, Nam SJ, Ahn YO, Keam B, Park HH, Kim DW, Kim CW, Heo DS
Title Novel JAK3-Activating Mutations in Extranodal NK/T-Cell Lymphoma, Nasal Type.
Journal The American journal of pathology
Vol 187
Issue 5
Date 2017 May
URL
Abstract Text Inhibition of the Janus kinase (JAK)-STAT pathway has been implicated as a treatment option for extranodal natural killer/T-cell lymphoma, nasal type (NTCL). However, JAK-STAT pathway alterations in NTCL are variable, and the efficacy of JAK-STAT pathway inhibition has been poorly evaluated. JAK3 mutation and STAT3 genetic alterations were investigated by direct sequencing and immunohistochemistry in 84 patients with newly diagnosed NTCL. Five of 71 patients with NTCL (7.0%) had JAK3 mutations in the pseudokinase domain: two JAK3A573V, two JAK3H583Y, and one JAK3G589D mutation. Proliferation of Ba/F3 cells transduced with novel JAK3 mutations (JAK3H583Y and JAK3G589D) was independent of IL-3 and was inhibited by the JAK3 inhibitor tofacitinib (means ± SD drug concentration causing a 50% inhibition of the desired activity, 85 ± 10 nmol/L and 54 ± 9 nmol/L). Ribbon diagrams revealed that these JAK3 pseudokinase domain mutations were located at the pseudokinase-kinase domain interface. Although phosphorylated STAT3 was overexpressed in 35 of 68 patients with NTCL (51.4%), a STAT3 mutation (p.Tyr640Phe; STAT3Y640F) at the SRC homology 2 domain was detected in 1 of the 63 patients (1.5%). A STAT3 inhibitor was active against STAT3-mutant SNK-6 and YT cells. Novel JAK3 mutations are oncogenic and druggable in NTCL. The JAK3 or STAT3 signal was altered in NTCL, and pathway inhibition might be a therapeutic option for patients with JAK3- or STAT3-mutant NTCL.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
JAK3 NCBI JAK-3|JAK3_HUMAN|JAKL|L-JAK|LJAK JAK3, Janus kinase 3, is a non-receptor protein tyrosine kinase involved in the interferon-alpha/beta/gamma pathway and is a member of the JAK/STAT signaling pathway (PMID: 15575979). JAK3 gain of function mutations are commonly observed in T-cell leukemias and lymphomas (PMID: 30079384, PMID: 30250904, PMID: 28284718). Oncogene
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 the 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), and leads to cytokine-independent proliferation of cultured cells (PMID: 22705984, PMID: 28284718).
JAK3 A573V missense gain of function JAK3 A573V lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). A573V results in constitutive phosphorylation of Jak3, activation of downstream Stat5 and Erk, is transforming in cultured cells (PMID: 18755984, PMID: 29046866, PMID: 28284718), and induces T-cell acute lymphoblastic leukemia in mouse models (PMID: 25193870).
JAK3 G589D missense gain of function - predicted JAK3 G589D lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). G589D has not been biochemically characterized, but demonstrates transformation of cells in culture (PMID: 28284718), and therefore, is predicted to lead to a gain of Jak3 protein function.
JAK3 H583Y missense gain of function - predicted JAK3 H583Y lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). H538Y has not been biochemically characterized, but demonstrates transformation of cells in culture (PMID: 28284718), and therefore, is predicted to lead to a gain of function Jak3 protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK3 G589D hematologic cancer sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, Xeljanz (tofacitinib, CP-690,550) decreased cell viability in transformed mouse Ba/F3 cells expressing Jak3 G589D (PMID: 28284718). 28284718
JAK3 H583Y hematologic cancer sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, Xeljanz (tofacitinib, CP-690,550) decreased cell viability in transformed mouse Ba/F3 cells expressing Jak3 H538Y (PMID: 28284718). 28284718