Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations

T D Buitenkamp, R Pieters, N E Gallimore, A van der Veer, J P P Meijerink, H B Beverloo, M Zimmermann, V de Haas, S M Richards, A J Vora, C D Mitchell, L J Russell, C Schwab, C J Harrison, A V Moorman, M M van den Heuvel-Eibrink, M L den Boer, C M Zwaan

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78 Citations (Scopus)


Children with Down's syndrome (DS) have an increased risk of developing acute lymphoblastic leukemia (ALL) and have a low frequency of established genetic aberrations. We aimed to determine which genetic abnormalities are involved in DS ALL. We studied the frequency and prognostic value of deletions in B-cell development genes and aberrations of janus kinase 2 (JAK2) and cytokine receptor-like factor 2 (CRLF2) using array-comparative genomic hybridization, and multiplex ligation-dependent probe amplification in a population-based cohort of 34 Dutch Childhood Oncology Group DS ALL samples. A population-based cohort of 88 DS samples from the UK trials was used to validate survival estimates for IKZF1 and CRLF2 abnormalities. In total, 50% of DS ALL patients had ≥1 deletion in the B-cell development genes: PAX5 (12%), VPREB1 (18%) and IKZF1 (35%). JAK2 was mutated in 15% of patients, genomic CRLF2 rearrangements in 62%. Outcome was significantly worse in patients with IKZF1 deletions (6-year event-free survival (EFS) 45 ± 16% vs 95 ± 4%; P=0.002), which was confirmed in the validation cohort (6-year EFS 21 ± 12% vs 58 ± 11%; P=0.002). This IKZF1 deletion was a strong independent predictor for outcome (hazard ratio EFS 3.05; P=0.001). Neither CRLF2 nor JAK2 were predictors for worse prognosis. If confirmed in prospective series, IKZF1 deletions may be used for risk-group stratification in DS ALL.

Original languageEnglish
Pages (from-to)2204-11
Number of pages8
Issue number10
Publication statusPublished - Oct 2012
Externally publishedYes


  • Child, Preschool
  • Comparative Genomic Hybridization
  • Down Syndrome/complications
  • Female
  • Gene Deletion
  • Gene Expression Profiling
  • Humans
  • Ikaros Transcription Factor/genetics
  • In Situ Hybridization, Fluorescence
  • Janus Kinase 2/genetics
  • Male
  • Multivariate Analysis
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma/etiology
  • Receptors, Cytokine/genetics


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