Reference Detail

Ref Type

Journal Article

PMID

(18397343)

Authors

Sato T, Toki T, Kanezaki R, Xu G, Terui K, Kanegane H, Miura M, Adachi S, Migita M, Morinaga S, Nakano T, Endo M, Kojima S, Kiyoi H, Mano H, Ito E

Title

Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukaemia accompanying Down syndrome.

Journal	Vol	Issue	Date	Pages	Journal Short Title
British journal of haematology	141	5	2008 May	681-8	Br J Haematol

URL

Abstract Text

JAK3 mutations have been reported in transient myeloproliferative disorder (TMD) as well as in acute megakaryoblastic leukaemia of Down syndrome (DS-AMKL). However, functional consequences of the JAK3 mutations in TMD patients remain undetermined. To further understand how JAK3 mutations are involved in the development and/or progression of leukaemia in Down syndrome, additional TMD patients and the DS-AMKL cell line MGS were screened for JAK3 mutations, and we examined whether each JAK3 mutation is an activating mutation. JAK3 mutations were not detected in 10 TMD samples that had not previously been studied. Together with our previous report we detected JAK3 mutations in one in 11 TMD patients. Furthermore, this study showed for the first time that a TMD patient-derived JAK3 mutation (JAK3(I87T)), as well as two novel JAK3 mutations (JAK3(Q501H) and JAK3(R657Q)) identified in an MGS cell line, were activating mutations. Treatment of MGS cells and Ba/F3 cells expressing the JAK3 mutants with JAK3 inhibitors significantly decreased their growth and viability. These results suggest that the JAK3 activating mutation is an early event during leukaemogenesis in Down syndrome, and they provide proof-of-principle evidence that JAK3 inhibitors would have therapeutic effects on TMD and DS-AMKL patients carrying activating JAK3 mutations.

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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	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	Q501H	missense	gain of function	JAK3 Q501H does not lie within any known functional domains of the Jak3 protein (UniProt.org). Q501H confers a gain of function to Jak3, as indicated by phosphorylation of downstream Stat5, and is transforming in cell culture (PMID: 18397343, PMID: 20400977).
JAK3	R657Q	missense	gain of function	JAK3 R657Q lies within protein kinase domain 1 of the Jak3 protein (UniProt.org). R657Q confers a gain of function to Jak3, as indicated by phosphorylation of downstream Stat5, and is transforming in cell culture (PMID: 18397343, PMID: 20400977).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
JAK3 I87T	Advanced Solid Tumor	sensitive	JANEX-1	Preclinical - Cell culture	Actionable	In a preclinical study, JANEX-1 (WHI-P131) inhibited proliferation of transformed cells expressing JAK3 I87T in culture (PMID: 18397343).	18397343