TY - JOUR
T1 - Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia
AU - Mullighan, Charles G.
AU - Su, Xiaoping
AU - Zhang, Jinghui
AU - Radtke, Ina
AU - Phillips, Letha A.A.
AU - Miller, Christopher B.
AU - Ma, Jing
AU - Liu, Wei
AU - Cheng, Cheng
AU - Schulman, Brenda A.
AU - Harvey, Richard C.
AU - Chen, I. Ming
AU - Clifford, Robert J.
AU - Carroll, William L.
AU - Reaman, Gregory
AU - Bowman, W. Paul
AU - Devidas, Meenakshi
AU - Gerhard, Daniela S.
AU - Yang, Wenjian
AU - Relling, Mary V.
AU - Pharm, D.
AU - Shurtleff, Sheila A.
AU - Campana, Dario
AU - Borowitz, Michael J.
AU - Pui, Ching Hon
AU - Smith, Malcolm
AU - Hunger, Stephen P.
AU - Willman, Cheryl L.
AU - Downing, James R.
PY - 2009/1/29
Y1 - 2009/1/29
N2 - 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-progen-itor ALL.
AB - 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-progen-itor ALL.
UR - http://www.scopus.com/inward/record.url?scp=58749109707&partnerID=8YFLogxK
U2 - 10.1056/NEJMoa0808253
DO - 10.1056/NEJMoa0808253
M3 - Article
C2 - 19129520
AN - SCOPUS:58749109707
SN - 0028-4793
VL - 360
SP - 470
EP - 480
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 5
ER -