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

Journal article

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.

Authors: Buitenkamp, T; Pieters, R; Gallimore, N; van der Veer, A; Meijerink, J

• Publication status: Published
• Journal: Leukemia
• Volume: 26
• Issue: 10
• Pages: 2204-2211
• Publication date: 2012-10-01
• DOI: 10.1038/leu.2012.84
• EISSN: 1476-5551
• ISSN: 0887-6924
• Language: English
• Keywords: Receptors, Cytokine; Janus Kinase 2; Female; Ikaros Transcription Factor; Gene Expression Profiling; Male; Comparative Genomic Hybridization; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Down Syndrome; Child, Preschool; Multivariate Analysis; Gene Deletion; In Situ Hybridization, Fluorescence