Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia.
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.
Mullighan
Charles G
CG
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Su
Xiaoping
X
Zhang
Jinghui
J
Radtke
Ina
I
Phillips
Letha A A
LA
Miller
Christopher B
CB
Ma
Jing
J
Liu
Wei
W
Cheng
Cheng
C
Schulman
Brenda A
BA
Harvey
Richard C
RC
Chen
I-Ming
IM
Clifford
Robert J
RJ
Carroll
William L
WL
Reaman
Gregory
G
Bowman
W Paul
WP
Devidas
Meenakshi
M
Gerhard
Daniela S
DS
Yang
Wenjian
W
Relling
Mary V
MV
Shurtleff
Sheila A
SA
Campana
Dario
D
Borowitz
Michael J
MJ
Pui
Ching-Hon
CH
Smith
Malcolm
M
Hunger
Stephen P
SP
Willman
Cheryl L
CL
Downing
James R
JR
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
C081976:EBF1 protein, human; C497239:IKZF1 protein, human; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D015534:Trans-Activators; D051740:Ikaros Transcription Factor