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Ref Type Journal Article
PMID (29046866)
Authors Martinez GS, Ross JA, Kirken RA
Title Transforming Mutations of Jak3 (A573V and M511I) Show Differential Sensitivity to Selective Jak3 Inhibitors.
Journal Clinical cancer drugs
Vol 3
Issue 2
Date 2016
URL
Abstract Text A medical need exists for successfully treating patients afflicted with leukemia and especially those that relapse and ultimately become refractory to front line chemotherapies. Leukemia cases are particularly high within Hispanic populations where this disease is among the most frequently occurring cancer. A possible cause is somatic mutations in Janus tyrosine kinase (Jak3). Fourteen somatic mutations have been reported in Jak3, including M511I and A573V, from patients with various forms of leukemia. While several of these Jak3 mutations have been shown to possess transforming ability in cell lines, whether these mutations are susceptible to Jak3 selective inhibitors remains less clear.The IL-3 dependent pro-B cell line Ba/F3 was virally transduced with plasmids encoding GFP and different mutant forms of Jak3, some of which conferred IL-3 independence. Sensitivity to pre-clinical and clinical Jak3 selective inhibitors was assessed for cellular viability and growth.Two Jak3 mutations conferred IL-3 independent growth in Ba/F3 cells. However, the level of drug sensitivity varied with respect to Jak3 inhibitors NC1153, CP-690,550, and EP-009.Jak3 inhibitors CP-690,550 and NC1153 showed efficacy in reducing viability of Ba/F3 cells transformed with mutant forms of Jak3, thus providing new therapeutic strategies to treat these types of cancer.

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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 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 A593T missense no effect - predicted JAK3 A593T lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). A593T has not been biochemically characterized, but is not transforming in cell culture (PMID: 29046866), and therefore, is predicted to have no effect on Jak3 protein function.
JAK3 G62S missense gain of function JAK3 G62S lies within the FERM domain of the Jak3 protein (UniProt.org). G62S confers a gain of function to the Jak3 protein, as demonstrated by increased autophosphorylation of Jak3, Stat5 activation (PMID: 29046866), and is weakly transforming in cell culture (PMID: 20400977).
JAK3 I87T missense gain of function JAK3 I87T lies within the FERM domain of the Jak3 protein (UniProt.org). I87T confers a gain of function to Jak3, as demonstrated by increased Jak3 autophosphorylation (PMID: 29046866), constitutive phosphorylation of downstream Stat5, and is transforming in cell culture (PMID: 18397343).
JAK3 K855A missense loss of function JAK3 K855A lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). K855A confers a loss of function to the Jak3 protein, as demonstrated by loss of phosphorylase activity (PMID: 29046866, PMID: 11741532, PMID: 14615376), and the lack of IL-2-dependent Stat5 activation in cell culture (PMID: 10629052).
JAK3 L1017M missense unknown JAK3 L1017M lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). L1017M results in transformation of cells in one study (PMID: 20400977) but does not transform cells in another study (PMID: 29046866), and therefore, its effect on Jak3 protein function is unknown.
JAK3 M511I missense gain of function JAK3 M511I does not lie within any known functional domains of the Jak3 protein (UniProt.org). M511I results in increased phosphorylation of Jak3, activation of Stat5 and Erk signaling, enhanced tumor growth in animal models, and is transforming in cell culture (PMID: 25193870, PMID: 28852199, PMID: 20400977, PMID: 29046866).
JAK3 M576L missense gain of function - predicted JAK3 M576L lies within the protein kinase domain 1 of the Jak3 protein (UniProt.org). M576L results in increased Jak3 autophosphorylation and is capable of phosphorylating Stat5 (PMID: 29046866), and therefore, is predicted to lead to a gain of Jak3 protein function.
JAK3 P132T missense gain of function JAK3 P132T lies within the FERM domain of the Jak3 protein (UniProt.org). P132T confers a gain of function to the Jak3 protein, as demonstrated by increased Jak3 autophosphorylation, Stat5 activation (PMID: 29046866), and increased cell proliferation in culture (PMID: 16843266).
JAK3 R918C missense unknown JAK3 R918C lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). R918C results in transformation of cells in one study (PMID: 20400977) but does not transform cells in another study (PMID: 29046866), and therefore, its effect on Jak3 protein function is unknown.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK3 M511I 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 M511I (PMID: 29046866). 29046866
JAK3 A573V 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 A573V (PMID: 29046866). 29046866