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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 British journal of haematology
Vol 141
Issue 5
Date 2008 May
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 Associated with drug Resistance
JAK3 I87T missense gain of function JAK3 I87T lies within the FERM domain of the Jak3 protein ( 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 ( 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 the protein kinase domain 1 of the Jak3 protein ( 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