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

Lookup NU author(s): Dr Lisa Russell, Claire Schwab, Professor Christine Harrison FRCPath FMedSci, Professor Anthony MoormanORCiD


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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. Leukemia (2012) 26, 2204-2211; doi:10.1038/leu.2012.84

Publication metadata

Author(s): Buitenkamp TD, Pieters R, Gallimore NE, van der Veer A, Meijerink JPP, Beverloo HB, Zimmermann M, de Haas V, Richards SM, Vora AJ, Mitchell CD, Russell LJ, Schwab C, Harrison CJ, Moorman AV, van den Heuvel-Eibrink MM, den Boer ML, Zwaan CM

Publication type: Article

Publication status: Published

Journal: Leukemia

Year: 2012

Volume: 26

Issue: 10

Pages: 2204-2211

Print publication date: 20/04/2012

ISSN (print): 0887-6924

ISSN (electronic): 1476-5551

Publisher: Nature Publishing Group


DOI: 10.1038/leu.2012.84


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Funder referenceFunder name
foundation Kinderen Kankervrij (KIKA)
Leukaemia and Lymphoma Research (LLR)
EMCR 2007-3718Dutch Cancer Society