Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer drugs	3	2	2016	131-137	Clin Cancer Drugs

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
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).
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 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 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 protein kinase domain 1 of the Jak3 protein (UniProt.org). M576L results in increased Jak3 autophosphorylation and is capable of phosphorylating Stat5 in culture (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 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