title: Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukaemia accompanying Down syndrome.
abstract: 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.
authors.affiliation: Department of Paediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Sato
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Toki
authors.forename: Rika
authors.initials: R
authors.lastname: Kanezaki
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.forename: Kiminori
authors.initials: K
authors.lastname: Terui
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kanegane
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Miura
authors.forename: Souichi
authors.initials: S
authors.lastname: Adachi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Migita
authors.forename: Shingo
authors.initials: S
authors.lastname: Morinaga
authors.forename: Takahide
authors.initials: T
authors.lastname: Nakano
authors.forename: Mikiya
authors.initials: M
authors.lastname: Endo
authors.forename: Seiji
authors.initials: S
authors.lastname: Kojima
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kiyoi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mano
authors.forename: Etsuro
authors.initials: E
authors.lastname: Ito
mesh_terms: D001483:Base Sequence; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004314:Down Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D007947:Leukemia, Megakaryoblastic, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D009363:Neoplasm Proteins; D011799:Quinazolines; C116180:WHI P131; C507933:JAK3 protein, human; D053616:Janus Kinase 3