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Acute Leukemias

IKZF1 deletions predict relapse in uniformly treated pediatric precursor B-ALL

Leukemia volume 24, pages 1258–1264 (2010)Cite this article

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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 ∼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.

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Acknowledgements

We thank Drs Ellen van der Schoot, Jeltje de Vries, Peggy Manders, Paul N Span, Jayne Hehir-Kwa, Suzanne T M Keijzers-Vloet and Eugène Verwiel for their advice and support. This work was supported by grants from the Dutch Cancer Society (KUN2009-4298; RPK, AGvK and PMH), KiKa (FNvL, PMH and RPK) and the Quality of Life Gala Foundation (PMH, FNvL, AGvK and RPK).

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Author notes

  1. R P Kuiper and E Waanders: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Human Genetics,

    R P Kuiper, E Waanders, S V van Reijmersdal, R Venkatachalam & A Geurts van Kessel

  2. Radboud University Nijmegen Medical Centre and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands

    R P Kuiper, E Waanders, S V van Reijmersdal, R Venkatachalam & A Geurts van Kessel

  3. Department of Immunology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands

    V H J van der Velden & J J M van Dongen

  4. Department of Pediatric Hemato-Oncology, Radboud University Nijmegen Medical Centre and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands

    B Scheijen, F N van Leeuwen & P M Hoogerbrugge

  5. Dutch Childhood Oncology Group, The Hague, The Netherlands

    E Sonneveld, A J P Veerman & P M Hoogerbrugge

  6. Department of Paediatric Oncology, VU University Medical Centre, Amsterdam, The Netherlands

    A J P Veerman

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  1. R P Kuiper
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Correspondence to R P Kuiper.

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Additional information

The SNP array data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE 20353.

Supplementary Information accompanies the paper on the Leukemia website

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Kuiper, R., Waanders, E., van der Velden, V. et al. IKZF1 deletions predict relapse in uniformly treated pediatric precursor B-ALL. Leukemia 24, 1258–1264 (2010). https://doi.org/10.1038/leu.2010.87

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