title: JAK mutations in high-risk childhood acute lymphoblastic leukemia.
abstract: Pediatric acute lymphoblastic leukemia (ALL) is a heterogeneous disease consisting of distinct clinical and biological subtypes that are characterized by specific chromosomal abnormalities or gene mutations. Mutation of genes encoding tyrosine kinases is uncommon in ALL, with the exception of Philadelphia chromosome-positive ALL, where the t(9,22)(q34;q11) translocation encodes the constitutively active BCR-ABL1 tyrosine kinase. We recently identified a poor prognostic subgroup of pediatric BCR-ABL1-negative ALL patients characterized by deletion of IKZF1 (encoding the lymphoid transcription factor IKAROS) and a gene expression signature similar to BCR-ABL1-positive ALL, raising the possibility of activated tyrosine kinase signaling within this leukemia subtype. Here, we report activating mutations in the Janus kinases JAK1 (n = 3), JAK2 (n = 16), and JAK3 (n = 1) in 20 (10.7%) of 187 BCR-ABL1-negative, high-risk pediatric ALL cases. The JAK1 and JAK2 mutations involved highly conserved residues in the kinase and pseudokinase domains and resulted in constitutive JAK-STAT activation and growth factor independence of Ba/F3-EpoR cells. The presence of JAK mutations was significantly associated with alteration of IKZF1 (70% of all JAK-mutated cases and 87.5% of cases with JAK2 mutations; P = 0.001) and deletion of CDKN2A/B (70% of all JAK-mutated cases and 68.9% of JAK2-mutated cases). The JAK-mutated cases had a gene expression signature similar to BCR-ABL1 pediatric ALL, and they had a poor outcome. These results suggest that inhibition of JAK signaling is a logical target for therapeutic intervention in JAK mutated ALL.
authors.affiliation: Departments of Pathology and Biostatistics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhang
authors.forename: Richard C
authors.initials: RC
authors.lastname: Harvey
authors.forename: J Racquel
authors.initials: JR
authors.lastname: Collins-Underwood
authors.forename: Brenda A
authors.initials: BA
authors.lastname: Schulman
authors.forename: Letha A
authors.initials: LA
authors.lastname: Phillips
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Tasian
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Su
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Devidas
authors.forename: Susan R
authors.initials: SR
authors.lastname: Atlas
authors.forename: I-Ming
authors.initials: IM
authors.lastname: Chen
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Clifford
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Gerhard
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Reaman
authors.forename: Malcolm
authors.initials: M
authors.lastname: Smith
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
mesh_terms: D002648:Child; D020869:Gene Expression Profiling; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism; D053613:Janus Kinase 1 / Q000235:genetics* / Q000378:metabolism; D053616:Janus Kinase 3 / Q000235:genetics* / Q000378:metabolism; D053612:Janus Kinases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C497239:IKZF1 protein, human; D051740:Ikaros Transcription Factor; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D053612:Janus Kinases