1. ¹Hematologic Section of the Human Genetics Centre, Cliniques universitaires UCL Saint-Luc, Brussels, Belgium
2. ²Human Genetics - Department of Molecular and Developmental Genetics, VIB, Leuven, Belgium
3. ³Department of Hematology, Cliniques universitaires UCL de Mont-Godinne, Yvoir, Belgium
4. ⁴Centre for Human Genetics, University of Leuven, Leuven, Belgium
5. ⁵Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
6. ⁶Département de Génétique, CHU Timone, Marseille, France
7. ⁷Laboratoire d'Hématologie - Génétique des Hémopathies, Hôpital Purpan, Toulouse, France
8. ⁸Leukemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
9. ⁹Laboratoire de Cytogénétique, CHU Le Bocage, Dijon, France
10. ¹⁰Laboratoire d'Hématologie, Hôpital Haute Pierre, Strasbourg, France
11. ¹¹Laboratoire de Génétique, CHU de Nancy-Brabois, Vandoeuvre-Les-Nancy, France
12. ¹²Laboratoire d'Hématologie - Pavillon de Biologie, CHU Hôpital Nord, St Etienne, France
13. ¹³Laboratoire d'Hématologie, CHU de Bordeaux, Bordeaux, France
14. ¹⁴Laboratoire d'Hématologie – Génétique moléculaire et chromosomique, Hôpital Arnaud de Villeneuve, Montpellier, France
15. ¹⁵Leukemia Research Cytogenetics Group, Cancer Sciences Division, University of Southampton, Southampton, UK

Correspondence: Dr C Graux, Department of Hematology, Cliniques universitaires UCL de Mont-Godinne, Avenue Therasse 1, B-5530, Yvoir, Belgium. E-mail: carlos.graux@uclouvain.be

¹⁶A Hagemeijer and HA Poirel are senior authors.

Received 28 May 2008; Revised 24 July 2008; Accepted 29 August 2008; Published online 16 October 2008.

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.