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Acute Leukemias

An intragenic ERG deletion is a marker of an oncogenic subtype of B-cell precursor acute lymphoblastic leukemia with a favorable outcome despite frequent IKZF1 deletions

Leukemia volume 28, pages 70–77 (2014)Cite this article

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Abstract

Oncogenic subtypes in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are used for risk stratification. However, a significant number of BCP-ALL patients are still genetically unassigned. Using array-comparative genomic hybridization in a selected BCP-ALL cohort, we characterized a recurrent V(D)J-mediated intragenic deletion of the ERG gene (ERGdel). A breakpoint-specific PCR assay was designed and used to screen an independent non-selected cohort of 897 children aged 1–17 years treated for BCP-ALL in the EORTC-CLG 58951 trial. ERGdel was found in 29/897 patients (3.2%) and was mutually exclusive of known classifying genetic lesions, suggesting that it characterized a distinct leukemia entity. ERGdel was associated with higher age (median 7.0 vs 4.0 years, P=0.004), aberrant CD2 expression (43.5% vs 3.7%, P<0.001) and frequent IKZF1 Δ4-7 deletions (37.9% vs 5.3%, P<0.001). However, ERGdel patients had a very good outcome, with an 8-year event-free survival (8-y EFS) and an 8-year overall survival of 86.4% and 95.6%, respectively, suggesting that the IKZF1 deletion had no impact on prognosis in this genetic subtype. Accordingly, within patients with an IKZF1 Δ4-7 deletion, those with ERGdel had a better outcome (8-y EFS: 85.7% vs 51.3%; hazard ratio: 0.16; 95% confidence interval: 0.02–1.20; P=0.04). These findings have implications for further stratification including IKZF1 status.

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Acknowledgements

This work was supported by the Laurette Fugain foundation and the EORTC Charitable Trust. We thank Daniela Geromin from the St-Louis Hospital’s Tumor Biobank for managing patient biological samples. We thank Seraphine Rossi and Lies Mierlaen from EORTC Headquarters. We thank Mélanie Pannetier of the Hematology Laboratory, Robert Debré hospital. We thank S Rasika for English editing of the manuscript. We thank the many clinicians and biologists who took care of the patients enrolled in the EORTC-CLG 58951 study.

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Author notes

  1. J Soulier and H Cavé: Co-last authors.

  2. H Cavé: On behalf of the EORTC Children’s Leukemia Group.

Authors and Affiliations

  1. U944 INSERM and Hematology laboratory, St-Louis Hospital, APHP, Paris, France

    E Clappier, M-F Auclerc, L Hernandez, J-M Cayuela, F Sigaux & J Soulier

  2. Department of Genetics, Robert Debré Hospital, APHP, Paris, France

    E Clappier, A Caye, A Khemiri, C Giroux & H Cavé

  3. Hematology University Institute, University Paris-Diderot, Paris, France

    E Clappier, J-M Cayuela, F Sigaux, J Soulier & H Cavé

  4. Department of Pediatric Hematology, St-Louis Hospital, APHP, Paris, France

    M-F Auclerc & T Leblanc

  5. EORTC Headquarters, Brussels, Belgium

    J Rapion & S Suciu

  6. Molecular Hematology Laboratory, UZ Brussels, Brussels, Belgium

    M Bakkus & E Kabongo

  7. MRC-Holland, Amsterdam, The Netherlands

    S Savola

  8. Department of Pediatric Hematology, Robert-Debré Hospital, APHP, Paris, France

    K Yakouben

  9. Department of Pediatric Onco-Hematology, University Hospital Purpan, Toulouse, France

    G Plat

  10. Department of Pediatrics, Portuguese Oncology Institute, Porto, Portugal

    V Costa

  11. Department of Pediatric Onco-Hematology, Children’s University Hospital Reine Fabiola, Brussels, Belgium

    A Ferster

  12. Hematology Laboratory, IHOP, Lyon, France

    S Girard

  13. Hematology Laboratory, Robert Debré Hospital, APHP, Paris, France

    O Fenneteau

  14. Hematology Laboratory, University Hospital Purpan, Toulouse, France

    N Dastugue

  15. Department of Pediatric Hematology-Oncology, Ghent University Hospital, Ghent, Belgium

    Y Benoit

  16. Department of Pediatric Hematology, IHOP and Claude Bernard University, Lyon, France

    Y Bertrand

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Correspondence to J Soulier or H Cavé.

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SSa is employed by MRC-Holland. The remaining authors declare no conflict of interest.

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Clappier, E., Auclerc, MF., Rapion, J. et al. An intragenic ERG deletion is a marker of an oncogenic subtype of B-cell precursor acute lymphoblastic leukemia with a favorable outcome despite frequent IKZF1 deletions. Leukemia 28, 70–77 (2014). https://doi.org/10.1038/leu.2013.277

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