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Cytogenetics and Molecular Genetics

Heterogeneous patterns of amplification of the NUP214-ABL1 fusion gene in T-cell acute lymphoblastic leukemia

Abstract

Episomes with the NUP214-ABL1 fusion gene have been observed in 6% of T-ALL. In this multicentric study we collected 27 cases of NUP214-ABL1-positive T-ALL. Median age was 15 years with male predominance. Outcome was poor in 12 patients. An associated abnormality involving TLX1 or TLX3 was found in all investigated cases. Fluorescent in situ hybridization revealed a heterogeneous pattern of NUP214-ABL1 amplification. Multiple episomes carrying the fusion were detected in 24 patients. Episomes were observed in a significant number of nuclei in 18 cases, but in only 1–5% of nuclei in 6. In addition, intrachromosomal amplification (small hsr) was identified either as the only change or in association with episomes in four cases and two T-ALL cell lines (PEER and ALL-SIL). One case showed insertion of apparently non-amplified NUP214-ABL1 sequences at 14q12. The amplified sequences were analyzed using array-based CGH.

These findings confirm that the NUP214-ABL1 gene requires amplification for oncogenicity; it is part of a multistep process of leukemogenesis; and it can be a late event present only in subpopulations. Data also provide in vivo evidence for a model of episome formation, amplification and optional reintegration into the genome. Implications for the use of kinase inhibitors are discussed.

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Acknowledgements

The collaboration of the following persons is gratefully acknowledged: Eric Delabesse (Hôpital Purpan, Toulouse), Hélène Cavé (Hôpital Robert Debré, Paris), Nathalie Grardel (CHRU de Lille, Lille), Khéïra Beldjord (Hôpital Necker, Paris), Sylvie Tondeur (Hôpital Arnaud de Villeneuve, Montpellier), Michel Lessard (Hôpital Haute Pierre, Strasbourg), Nancy Boeckx (Gasthuisberg, KULeuven, Leuven), Pascale Saussoy (Cliniques universitaires UCL Saint-Luc, Brussels), Patrick Callier, François Girodon and Bernardine Favre-Audry (CHU Le Bocage, Dijon) for molecular and/or cytogenetic and/or cytological analyses; Dr Petra Muus (RUMC, Nijmegen), Dr Claire Galambrun and Dr Gérard Michel (CHU Timone, Marseilles), Dr Françoise Huguet (Hôpital Purpan, Toulouse), Dr Alain Robert (Hôpital des Enfants, Toulouse), Dr Olivier Boulat (CHG Avignon, Avignon), Dr Pierre Bordigoni (CHU Nancy-Brabois, Vandoeuvre-Les-Nancy), Dr Johan Maertens and Dr Anne Uyttebroeck (Gasthuisberg, KULeuven, Leuven), Dr Nathalie Fegueux (Hôpital Arnaud de Villeneuve, Montpellier), Dr Denis Caillot (CHU Le Bocage, Dijon) for clinical data.

The following members of the Groupe Francophone de Cytogénétique Hématologique provided samples: Carole Barin (CHU Tours, Tours), Roland Berger (Hôpital Necker, Paris), Chrystèle Bilhou-Nabera (Hôpital Bicêtre, Le Kremlin-Bicêtre), Christine Cabrol (Hôpital Cantonal Universitaire, Genève), Evelyne Callet-Bauchu (Centre Hospitalier Lyon Sud, Pierre Bénite), Pascale Cornillet-Lefebvre (Hôpital Robert Debré, Reims), Jean-Luc Laï (Hôpital Jeanne de Flandre, Lille), Christine Lefebvre (CHU Grenoble, Grenoble), Isabelle Luquet (Hôpital Robert Debré, Reims), Christine Perot (Hôpital Saint Antoine, Paris), Isabelle Radford-Weiss (Hôpital Necker-Enfants Malades, Paris), Frank Speleman (Ghent University Hospital, Ghent), Barabara Cauwelier (Ghent University Hospital, Ghent), Pascaline Talmant (CHU Nantes, Nantes), Christine Terré (CH Versailles, Versailles), Isabelle Tigaud (Centre Hospitalier Lyon Sud, Pierre Bénite); Jacqueline Van DenAkker (Hôpital Saint Antoine, Paris) and Franck Viguié (CHU Hôtel Dieu de Paris, Paris).

CJH, AVM and KB would like to thank the UK Cancer Cytogenetics Group (UKCCG), Clinical Trial Service Unit (CTSU, University of Oxford, UK), United Kingdom Children′s Cancer and Leukemia Group (CCLG) and the NCRI Adult Leukemia Working Party for their cooperation in collating these data.

CG is supported by a Grant from the ‘Fond National de la Recherche Scientifique (F.N.R.S.)’; ML, by the ‘Fondation contre la Leucémie de la Fondation de France’. This study was also partly supported by Grants from ‘Salus Sanguinis’, ‘Fond Maisin’ and ‘Centre du Cancer’ and by a concerted action Grant from the KULeuven. PV is senior clinical investigator, FWO, Belgium.

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Correspondence to C Graux.

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The work was done at Centre for Human Genetics, University of Leuven, Leuven, Belgium and Hematologic Section of the Genetics Centre, Cliniques universitaires UCL Saint-Luc, Brussels, Belgium.

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Graux, C., Stevens-Kroef, M., Lafage, M. et al. Heterogeneous patterns of amplification of the NUP214-ABL1 fusion gene in T-cell acute lymphoblastic leukemia. Leukemia 23, 125–133 (2009). https://doi.org/10.1038/leu.2008.278

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