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Biclonal and biallelic deletions occur in 20% of B-ALL cases with IKZF1 mutations

Leukemia volume 27, pages 503–507 (2013)Cite this article

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The IKZF1 gene encodes the Ikaros transcription factor, a key regulator of lymphocyte differentiation.1 IKZF1 is mutated in 20–30% of B-cell acute lymphoblastic leukemia (B-ALL) mostly by genomic deletions.2, 3, 4 Several reports have shown that IKZF1 deletions are associated with an adverse prognosis, especially in pediatric patients.3, 4, 5, 6, 7, 8, 9, 10 Ikaros mutations fall mainly into three types: (a) deletions of exons 4–7 (Δ4–7), which lead to the synthesis of the Ikaros-6 (Ik6) dominant-negative isoform; (b) deletions of exons 2–7 (Δ2–7), which delete the initiation codon and lead to haploinsufficiency; and (c) larger deletions of various sizes, which affect the coding exons (referred to below as ‘complete’ deletions). Thus, IKZF1 mutations have until now been separated into dominant-negative and haploinsufficient groups. Here we report that about 20% of B-ALL patients with IKZF1 mutations present two distinct deletions. These deletions are biallelic, leading to a complete loss of Ikaros function, or biclonal, marking distinct clones within the leukemia. These results highlight a more complex picture of IKZF1 loss of function in B-ALL than thought previously.

We identified 60 IKZF1 mutant alleles in 49 patients (24 adult and 25 pediatric patients; see Supplementary Table S1, and Figure 1b for the distribution of the mutations in the affected patients). Four patterns of mutations were seen: dominant-negative, haploinsufficient, biallelic or biclonal.

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Acknowledgements

We thank C Thibault and D Goidin (Agilent) for their help with the design of the microarray, F Augé for microarray processing, D Dembélé for helping with the microarray analysis, H Cavé, E Clappier and J Ghysdael for their discussions and critical reading of the manuscript. This work was supported by grants to P Kastner and S Chan from the Ligue Nationale contre le Cancer (équipe labellisée), from the Institut National du Cancer (no. 2011–144), and by institute funds from INSERM, CNRS and the University of Strasbourg. A Dupuis was supported by a fellowship from the Fondation ARC pour la Recherche sur le Cancer.

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Authors and Affiliations

  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964-CNRS UMR 7104, Université de Strasbourg, Illkirch, France

    A Dupuis, S Chan & P Kastner

  2. Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

    A Dupuis, M P Gaub, M Legrain, L Mauvieux, P Lutz & R Herbrecht

  3. Plate-forme Régionale INCa de Génétique Moléculaire des Cancers d'Alsace, Strasbourg, France

    M P Gaub, M Legrain, B Drenou & L Mauvieux

  4. Université de Strasbourg, Strasbourg, France

    M P Gaub, M Legrain, L Mauvieux, P Lutz, R Herbrecht & P Kastner

  5. Département d'Hématologie, Centre Hospitalier Emile Muller, Mulhouse, France

    B Drenou

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  1. A Dupuis
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Correspondence to P Kastner.

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Dupuis, A., Gaub, M., Legrain, M. et al. Biclonal and biallelic deletions occur in 20% of B-ALL cases with IKZF1 mutations. Leukemia 27, 503–507 (2013). https://doi.org/10.1038/leu.2012.204

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