title: IKZF1 deletions predict relapse in uniformly treated pediatric precursor B-ALL.
abstract: Relapse is the most common cause of treatment failure in pediatric acute lymphoblastic leukemia (ALL) and is often difficult to predict. To explore the prognostic impact of recurrent DNA copy number abnormalities on relapse, we performed high-resolution genomic profiling of 34 paired diagnosis and relapse ALL samples. Recurrent lesions detected at diagnosis, including PAX5, CDKN2A and EBF1, were frequently absent at relapse, indicating that they represent secondary events that may be absent in the relapse-prone therapy-resistant progenitor cell. In contrast, deletions and nonsense mutations in IKZF1 (IKAROS) were highly enriched and consistently preserved at the time of relapse. A targeted copy number screen in an unselected cohort of 131 precursor B-ALL cases, enrolled in the dexamethasone-based Dutch Childhood Oncology Group treatment protocol ALL9, revealed that IKZF1 deletions are significantly associated with poor relapse-free and overall survival rates. Separate analysis of ALL9-treatment subgroups revealed that non-high-risk (NHR) patients with IKZF1 deletions exhibited a approximately 12-fold higher relative relapse rate than those without IKZF1 deletions. Consequently, IKZF1 deletion status allowed the prospective identification of 53% of the relapse-prone NHR-classified patients within this subgroup and, therefore, serves as one of the strongest predictors of relapse at the time of diagnosis with high potential for future risk stratification.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. r.kuiper@antrg.umcn.nl
authors.forename: R P
authors.initials: RP
authors.lastname: Kuiper
authors.forename: E
authors.initials: E
authors.lastname: Waanders
authors.forename: V H J
authors.initials: VH
authors.lastname: van der Velden
authors.forename: S V
authors.initials: SV
authors.lastname: van Reijmersdal
authors.forename: R
authors.initials: R
authors.lastname: Venkatachalam
authors.forename: B
authors.initials: B
authors.lastname: Scheijen
authors.forename: E
authors.initials: E
authors.lastname: Sonneveld
authors.forename: J J M
authors.initials: JJ
authors.lastname: van Dongen
authors.forename: A J P
authors.initials: AJ
authors.lastname: Veerman
authors.forename: F N
authors.initials: FN
authors.lastname: van Leeuwen
authors.forename: A Geurts
authors.initials: AG
authors.lastname: van Kessel
authors.forename: P M
authors.initials: PM
authors.lastname: Hoogerbrugge
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics; D055028:Comparative Genomic Hybridization; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D020869:Gene Expression Profiling; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D007223:Infant; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D020411:Oligonucleotide Array Sequence Analysis; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D011379:Prognosis; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D018389:Codon, Nonsense; C497239:IKZF1 protein, human; D051740:Ikaros Transcription Factor