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Published at www.nejm.org January 7, 2009 (10.1056/NEJMoa0808253)

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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.

Source Information

From the Department of Pathology (C.G.M., X.S., I.R., L.A.A.P., C.B.M., S.A.S., D.C., J.R.D.), the Hartwell Center for Bioinformatics and Biotechnology (J.M.), the Department of Biostatistics (W.L., C.C.), the Department of Pharmaceutical Sciences (W.Y., M.V.R.), the Department of Structural Biology (B.A.S.), and the Department of Oncology (D.C., C.-H.P.), St. Jude Children's Research Hospital, Memphis, TN; the Center for Biomedical Informatics and Information Technology (J.Z.), the Laboratory of Population Genetics (R.J.C.), the Office of Cancer Genomics (D.S.G.), and the Cancer Therapy Evaluation Program (M.S.), National Cancer Institute, National Institutes of Health, Bethesda, MD; the Howard Hughes Medical Institute (B.A.S.) and the Department of Pathology (M.J.B.), Johns Hopkins Medical Institutions, Baltimore; University of New Mexico Cancer Research and Treatment Center, Albuquerque (R.C.H., I.-M.C., C.L.W.); New York University Cancer Institute, New York (W.L.C.); Children's National Medical Center, Washington, DC (G.R.); the Department of Hematology and Oncology, Cook Children's Medical Center, Fort Worth, TX (W.P.B.); the Department of Epidemiology and Health Policy Research, College of Medicine, University of Florida and the Children's Oncology Group, Gainesville (M.D.); and the University of Colorado Denver School of Medicine and the Children's Hospital, Aurora (S.P.H.).

This article (10.1056/NEJMoa0808253) was published at NEJM.org on January 7, 2009. It will appear in the January 29 issue of the Journal.

Address reprint requests to Dr. Downing at St. Jude Children's Research Hospital, 262 Danny Thomas Pl., MS 271, Memphis, TN 38105, or at james.downing{at}stjude.org.

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