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Deletion of IKZF1 and Prognosis in Acute Lymphoblastic Leukemia
Open accessAbstract
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.
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“In mice, both Ikzf1 and Ikzf3 are required for normal T cell development and maintenance of mature T cell populations88,89”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [89]
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Metadata
- Authors
- Mullighan, C. G., Su, X., Zhang, J., Radtke, I., Phillips, L. A. A., Miller, C. B., Ma, J., Liu, W., Cheng, C., Schulman, B. A., Harvey, R. C., Chen, I.-M., Clifford, R. J., Carroll, W. L., Reaman, G., Bowman, W. P., Devidas, M., Gerhard, D. S., Yang, W., Relling, M. V., Shurtleff, S. A., Campana, D., Borowitz, M. J., Pui, C.-H., Smith, M., Hunger, S. P., Willman, C. L., & Downing, J. R.
- Affiliations
- St. Jude Children's Research Hospital (US)
- National Institutes of Health (US)
- UNM Comprehensive Cancer Center (US)
- New York University (US)
- Children's National (US)
- Cook Children's Medical Center (US)
- University of Florida Health (US)
- Children's Hospital Colorado (US)
- ORCID
- Mullighan, Charles G.
- Su, Xiaoping
- Zhang, Jinghui
- Radtke, Ina
- Ma, Jing
- Liu, Wei
- Cheng, Cheng
- Schulman, Brenda A.
- Harvey, Richard C.
- Chen, I-Ming
- Clifford, Robert J.
- Carroll, William L.
- Reaman, Gregory
- Bowman, W. Paul
- Devidas, Meenakshi
- Yang, Wenjian
- Relling, Mary V.
- Campana, Dario
- Pui, Ching-Hon
- Smith, Malcolm
- Hunger, Stephen P.
- Willman, Cheryl L.
- Downing, James R.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2009-01-29
- Volume
- 360
- Issue
- 5
- Pages
- 470-480
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC2674612
- OpenAlex
- W2040329520
- Cited by
- 1,422
- References
- 37
- Citations by year
- 2026: 30 · 2025: 50 · 2024: 66 · 2023: 90 · 2022: 66 · 2021: 103 · 2020: 92 · 2019: 69 · 2018: 74 · 2017: 105 · 2016: 96 · 2015: 101 · 2014: 84 · 2013: 90 · 2012: 98
- FWCI
- 101.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Public Health Service (N01C012400, 21765)
- National Cancer Institute (CA 098543, R01CA086011, U10CA098413, U01CA157937, R01 CA86011, U10CA098543, U01CA114762, CA114762, P30CA021765)
- National Institute of General Medical Sciences (U01 GM61393, U01GM061374, U01-GM-61374, U01GM061393)
- Topics
- Health Sciences › Medicine › Hematology › Acute Lymphoblastic Leukemia research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- IKZF1 deletion, acute lymphoblastic leukemia, pediatric leukemia, copy number abnormalities, prognosis, PAX5, Ikaros, B cell development, gene expression signatures, relapse
- MeSH terms
- B-Lymphocytes, Child, DNA Mutational Analysis, Genotype, Hematopoietic Stem Cells, Humans, Prognosis, Recurrence, Cohort Studies, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Trans-Activators, Gene Expression, Treatment Outcome, Gene Deletion, Drug Resistance, Neoplasm, Mutation, Missense, Gene Expression Profiling, Ikaros Transcription Factor, PAX5 Transcription Factor
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