title: Ikaros (IKZF1) alterations and minimal residual disease at day 15 assessed by flow cytometry predict prognosis of childhood BCR/ABL-negative acute lymphoblastic leukemia.
abstract: BACKGROUND
  Recently, several studies have demonstrated a negative prognostic impact of Ikaros (IKZF1) gene alterations in acute lymphoblastic leukemia (ALL). However, controversies still exist regarding the impact of IKZF1 in current treatment protocols.
  
  
  METHODS
  We simultaneously detected IKZF1 gene deletions by multiplex ligation-dependent probe amplification and gene expression of IKZF1 isoforms in 206 children with BCR/ABL-negative ALL treated with ALL IC-BFM 2002 protocol, in which risk stratification was not based on minimal residual disease (MRD), and validated the results on a cohort of 189 patients treated with MRD-directed ALL-BFM 2000 protocol.
  
  
  RESULTS
  Deletion of IKZF1 was present in 14 of 206 (7%) ALL IC patients. Interestingly, gene expression did not completely correlate with the deletion status in either cohort. Deletions were not always reflected in the gene expression of dominant-negative isoforms, and conversely, 7 of 395 (2%) non-deleted cases overexpressed dominant-negative isoform Ik6. IKZF1 deletions significantly affected event-free survival (EFS) of the ALL IC cohort (41 ± 14% vs. 86 ± 3%, P < 0.0001). Regarding IKZF1 isoforms, only Ik6 overexpression had negative prognostic impact (EFS 50 ± 16% vs. 85 ± 3%, P = 0.003). In multivariate analysis, which included ALL IC risk criteria, flow-cytometric MRD and IKZF1 alterations, day 15 MRD and IKZF1 deletion status displayed an independent prognostic impact.
  
  
  CONCLUSIONS
  We show that MRD-directed treatment diminishes prognostic impact of IKZF1 alterations. However, IKZF1 status alone or combined with day 15 flow cytometry can significantly improve risk stratification within BFM protocols at centers that do not perform antigen-receptor-based MRD monitoring.
authors.affiliation: 2nd Faculty of Medicine, Department of Pediatric Hematology and Oncology, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Volejnikova
authors.forename: Ester
authors.initials: E
authors.lastname: Mejstrikova
authors.forename: Petra
authors.initials: P
authors.lastname: Dörge
authors.forename: Barbara
authors.initials: B
authors.lastname: Meissner
authors.forename: Olga
authors.initials: O
authors.lastname: Zimmermannova
authors.forename: Karel
authors.initials: K
authors.lastname: Svojgr
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.forename: Gunnar
authors.initials: G
authors.lastname: Cario
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.forename: Jan
authors.initials: J
authors.lastname: Stary
authors.forename: Ondrej
authors.initials: O
authors.lastname: Hrusak
authors.forename: Jan
authors.initials: J
authors.lastname: Trka
authors.forename: Eva
authors.initials: E
authors.lastname: Fronkova
mesh_terms: D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D008297:Male; D018365:Neoplasm, Residual / Q000235:genetics* / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D012307:Risk Factors; D059467:Transcriptome
chemical_list: C497239:IKZF1 protein, human; D051740:Ikaros Transcription Factor; D016044:Fusion Proteins, bcr-abl