Deletion of IKZF1 and Prognosis in Acute Lymphoblastic Leukemia

By C. Mullighan, X. Su, Jinghui Zhang, I. Radtke, Letha A A Phillips, C. Miller, Jing Ma, Wei Liu, Cheng Cheng, Brenda A Schulman and 18 more. New England Journal of Medicine, 2009

1,317 citations recorded by the source corpus.

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.

Subfields: Hematology, Public Health, Environmental and Occupational Health

View Paper: https://www.semanticscholar.org/paper/43df6b53b5efe24fb3413fc3020e22b85b28392e

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Citations in the corpus

• A Comprehensive Review (2017, neutral): “ted by IKZF1 gene deletion and IKZF1plus deletion pattern is also recognized and has been shown to confer a higher risk of relapse.(8,9) In 2009, both Mullighan and colleagues(8) and den Boer and colleagues(10) described a new subtype of B-ALL, which they termed Philadelphia chromosome–like and BCR-”
• Rearrangement of CRLF2 in B-progenitor– and Down syndrome–associated acute lymphoblastic leukemia (2009, neutral): “2,q32),add(9)(p13),+21c[6]/47,XY,+21c[4] 05 yes No 47,XX,+21c 06 no No 48,XX,+X,+21c[11]/47,XX,+21c[4] 07 yes No unavailable 08 no No 47,XX,+21c[15] 09 yes R683G 47,XX,+21[8]/46,XX[6] 10 yes No 47,XX,i(9)(q10),add(21)(p11.”
• JAK mutations in high-risk childhood acute lymphoblastic leukemia (2009, methodology): “Associations between clinical, laboratory, and genetic variables and outcome (event-free survival and relapse) were performed as described previously (4).”
• Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration. (2015, background): “In 2009, two groups of investigators using a different gene expression profiling approach identified a subtype of high-risk B ALL that lacked a known chromosomal rearrangement but exhibited a gene expression profile similar to that of Ph-positive ALL with deletions and, less commonly, sequence mutat”
• Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia (2012, background): “Genome-wide analyses have identified genetic alterations targeting transcriptional regulators of lymphoid development (PAX5, EBF1, and IKZF1) in over 60% of B-ALL patients (Kuiper et al., 2007; Mullighan et al., 2007, 2009b).”
• THE GENOMIC LANDSCAPE OF PEDIATRIC AND YOUNG ADULT T-LINEAGE ACUTE LYMPHOBLASTIC LEUKEMIA (2017, neutral): “Associations between T-ALL subtype and treatment outcome (event-free survival and overall survival) were done with the Kaplan–Meier estimator with Peto’s estimator of s.d. and the log-rank test 76–78 .”
• The genetic basis of early T-cell precursor acute lymphoblastic leukaemia (2012, background): “, and a signature of poor outcome in IKZF1 -mutated high-risk B-progenitor AL”
• A Compendium of Chromatin Contact Maps Reveal Spatially Active Regions in the Human Genome (2016, neutral): “29e-83) pair-wise Hi-C contact between a bin containing a SNP associated with acute lymphoblastic leukemia (ALL) (rs6964969) and a distal (∼130kb) TSS of IKZF1, a gene previously implicated in ALL (Mullighan et al., 2009) (Figure 6e, f).”
• Biology, risk stratification, and therapy of pediatric acute leukemias: an update. (2011, background): “Interestingly, there is a high-risk subgroup of BCR-ABL1– negative ALL that is characterized by IKZF1 deletion and has a genetic profile similar to that of cases with BCR-ABL1 fusion.(46,47) In search of activated tyrosine kinase signaling in this leukemic subtype, Mullighan et al(48) identified act”
• Targetable Kinase-Activating Lesions in Ph-like Acute Lymphoblastic Leukemia (2014, background): “Lengline E, Beldjord K, Dombret H, Soulier J, Boissel N, Clappier E. Successful tyrosine kinase inhibitor therapy in a refractory B-cell precursor acute lymphoblastic leukemia with EBF1-PDGFRB fusion.”