title: Identification of somatic JAK1 mutations in patients with acute myeloid leukemia.
abstract: Somatic mutations in JAK2 are frequently found in myeloproliferative diseases, and gain-of-function JAK3 alleles have been identified in M7 acute myeloid leukemia (AML), but a role for JAK1 in AML has not been described. We screened the entire coding region of JAK1 by total exonic resequencing of bone marrow DNA samples from 94 patients with de novo AML. We identified 2 novel somatic mutations in highly conserved residues of the JAK1 gene (T478S, V623A), in 2 separate patients and confirmed these by resequencing germ line DNA samples from the same patients. Overexpression of mutant JAK1 did not transform primary murine cells in standard assays, but compared with wild-type JAK1, JAK1(T478S), and JAK1(V623A) expression was associated with increased STAT1 activation in response to type I interferon and activation of multiple downstream signaling pathways. This is the first report to demonstrate somatic JAK1 mutations in AML and suggests that JAK1 mutations may function as disease-modifying mutations in AML pathogenesis.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, St Louis, MO 63110, USA.
authors.forename: Zhifu
authors.initials: Z
authors.lastname: Xiang
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.forename: Vesselin
authors.initials: V
authors.lastname: Mitaksov
authors.forename: Daved H
authors.initials: DH
authors.lastname: Fremont
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kasai
authors.forename: AnnaLynn
authors.initials: A
authors.lastname: Molitoris
authors.forename: Rhonda E
authors.initials: RE
authors.lastname: Ries
authors.forename: Tracie L
authors.initials: TL
authors.lastname: Miner
authors.forename: Michael D
authors.initials: MD
authors.lastname: McLellan
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Payton
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Graubert
authors.forename: Mark
authors.initials: M
authors.lastname: Watson
authors.forename: William
authors.initials: W
authors.lastname: Shannon
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Heath
authors.forename: Rakesh
authors.initials: R
authors.lastname: Nagarajan
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
authors.forename: Michael H
authors.initials: MH
authors.lastname: Tomasson
mesh_terms: D000818:Animals; D004252:DNA Mutational Analysis; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics*; D051379:Mice; D009154:Mutation; D020125:Mutation, Missense; D050794:STAT1 Transcription Factor / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D050794:STAT1 Transcription Factor; C507904:JAK1 protein, human; D053613:Janus Kinase 1