title: Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia.
abstract: BACKGROUND
  Despite best current therapy, up to 20% of pediatric patients with acute lymphoblastic leukemia (ALL) have a relapse. Recent genomewide analyses have identified a high frequency of DNA copy-number abnormalities in ALL, but the prognostic implications of these abnormalities have not been defined.
  
  
  METHODS
  We studied a cohort of 221 children with high-risk B-cell-progenitor ALL with the use of single-nucleotide-polymorphism microarrays, transcriptional profiling, and resequencing of samples obtained at diagnosis. Children with known very-high-risk ALL subtypes (i.e., BCR-ABL1-positive ALL, hypodiploid ALL, and ALL in infants) were excluded from this cohort. A copy-number abnormality was identified as a predictor of poor outcome, and it was then tested in an independent validation cohort of 258 patients with B-cell-progenitor ALL.
  
  
  RESULTS
  More than 50 recurring copy-number abnormalities were identified, most commonly involving genes that encode regulators of B-cell development (in 66.8% of patients in the original cohort); PAX5 was involved in 31.7% and IKZF1 in 28.6% of patients. Using copy-number abnormalities, we identified a predictor of poor outcome that was validated in the independent validation cohort. This predictor was strongly associated with alteration of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS. The gene-expression signature of the group of patients with a poor outcome revealed increased expression of hematopoietic stem-cell genes and reduced expression of B-cell-lineage genes, and it was similar to the signature of BCR-ABL1-positive ALL, another high-risk subtype of ALL with a high frequency of IKZF1 deletion.
  
  
  CONCLUSIONS
  Genetic alteration of IKZF1 is associated with a very poor outcome in B-cell-progenitor ALL.
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Su
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhang
authors.forename: Ina
authors.initials: I
authors.lastname: Radtke
authors.forename: Letha A A
authors.initials: LA
authors.lastname: Phillips
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Miller
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.forename: Brenda A
authors.initials: BA
authors.lastname: Schulman
authors.forename: Richard C
authors.initials: RC
authors.lastname: Harvey
authors.forename: I-Ming
authors.initials: IM
authors.lastname: Chen
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Clifford
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
authors.forename: Gregory
authors.initials: G
authors.lastname: Reaman
authors.forename: W Paul
authors.initials: WP
authors.lastname: Bowman
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Devidas
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Gerhard
authors.forename: Wenjian
authors.initials: W
authors.lastname: Yang
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Shurtleff
authors.forename: Dario
authors.initials: D
authors.lastname: Campana
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Borowitz
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: Malcolm
authors.initials: M
authors.lastname: Smith
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D017353:Gene Deletion; D015870:Gene Expression; D020869:Gene Expression Profiling; D005838:Genotype; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D020125:Mutation, Missense; D051757:PAX5 Transcription Factor / Q000235:genetics; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics*; D011379:Prognosis; D012008:Recurrence; D015534:Trans-Activators / Q000235:genetics; D016896:Treatment Outcome
chemical_list: C081976:EBF1 protein, human; C497239:IKZF1 protein, human; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D015534:Trans-Activators; D051740:Ikaros Transcription Factor