title: Tyrosine kinome sequencing of pediatric acute lymphoblastic leukemia: a report from the Children's Oncology Group TARGET Project.
abstract: One recently identified subtype of pediatric B-precursor acute lymphoblastic leukemia (ALL) has been termed BCR-ABL1-like or Ph-like because of similarity of the gene expression profile to BCR-ABL1 positive ALL suggesting the presence of lesions activating tyrosine kinases, frequent alteration of IKZF1, and poor outcome. Prior studies demonstrated that approximately half of these patients had genomic lesions leading to CRLF2 overexpression, with half of such cases harboring somatic mutations in the Janus kinases JAK1 and JAK2. To determine whether mutations in other tyrosine kinases might also occur in ALL, we sequenced the tyrosine kinome and downstream signaling genes in 45 high-risk pediatric ALL cases with either a Ph-like gene expression profile or other alterations suggestive of activated kinase signaling. Aside from JAK mutations and 1 FLT3 mutation, no somatic mutations were found in any other tyrosine kinases, suggesting that alternative mechanisms are responsible for activated kinase signaling in high-risk ALL.
authors.affiliation: Department of Pediatrics and the Helen Diller Family Cancer Center, University of California-San Francisco, CA, USA.
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhang
authors.forename: Richard C
authors.initials: RC
authors.lastname: Harvey
authors.forename: Kathryn
authors.initials: K
authors.lastname: Roberts
authors.forename: Debbie
authors.initials: D
authors.lastname: Payne-Turner
authors.forename: Huining
authors.initials: H
authors.lastname: Kang
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.forename: Jared
authors.initials: J
authors.lastname: Becksfort
authors.forename: Michael
authors.initials: M
authors.lastname: Edmonson
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Buetow
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
authors.forename: I-Ming
authors.initials: IM
authors.lastname: Chen
authors.forename: Brent
authors.initials: B
authors.lastname: Wood
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Borowitz
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Devidas
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Gerhard
authors.forename: Paul
authors.initials: P
authors.lastname: Bowman
authors.forename: Eric
authors.initials: E
authors.lastname: Larsen
authors.forename: Naomi
authors.initials: N
authors.lastname: Winick
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Raetz
authors.forename: Malcolm
authors.initials: M
authors.lastname: Smith
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
mesh_terms: D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology*; D006801:Humans; D007223:Infant; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D008297:Male; D018365:Neoplasm, Residual / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D058470:Receptors, Purinergic P2Y / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D059467:Transcriptome; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism
chemical_list: C498762:CRLF2 protein, human; C578279:P2RY8 protein, human; D018121:Receptors, Cytokine; D058470:Receptors, Purinergic P2Y; C497970:FLT3 protein, human; D011505:Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2