title: Loss-of-function JAK3 mutations in TMD and AMKL of Down syndrome.
abstract: Acquired mutations activating Janus kinase 3 (jak3) have been reported in Down syndrome (DS) and non-DS patients with acute megakaryoblastic leukaemia (AMKL). This highlighted jak3-activation as an important event in the pathogenesis of AMKL, and predicted inhibitors of jak3 as conceptual therapeutics for AMKL. Of 16 DS-transient myeloproliferative disorder (TMD)/AMKL patients tested, seven showed JAK3 mutations. Three mutations deleted the kinase (JH1) domain, abolishing the main function of jak3. Another patient displayed a mutation identical to a previously reported inherited loss-of-function causing severe combined immunodeficiency. Our data suggest that both gain-, and loss-of function mutations of jak3 can be acquired in DS-TMD/AMKL.
authors: Centre for Haematology, Institute of Cell and Molecular Science, Barts & The London, Queen Mary's School of Medicine, University of London, London, UK.
authors: Serena
authors: S
authors: De Vita
authors: Claire
authors: C
authors: Mulligan
authors: Suzanne
authors: S
authors: McElwaine
authors: Franca
authors: F
authors: Dagna-Bricarelli
authors: Monica
authors: M
authors: Spinelli
authors: Giuseppe
authors: G
authors: Basso
authors: Dean
authors: D
authors: Nizetic
authors: Jürgen
authors: J
authors: Groet
mesh_terms: D001483:Base Sequence; D004314:Down Syndrome / Q000235:genetics* / Q000276:immunology; D004789:Enzyme Activation; D017353:Gene Deletion; D006801:Humans; D053616:Janus Kinase 3 / Q000235:genetics*; D007947:Leukemia, Megakaryoblastic, Acute / Q000150:complications / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: D011505:Protein-Tyrosine Kinases; D053616:Janus Kinase 3