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ORIGINAL ARTICLE Heterogeneous Patterns of Amplification of The Leukemia (2009) 23, 125–133 & 2009 Macmillan Publishers Limited All rights reserved 0887-6924/09 $32.00 www.nature.com/leu ORIGINAL ARTICLE Heterogeneous patterns of amplification of the NUP214-ABL1 fusion gene in T-cell acute lymphoblastic leukemia C Graux1,2,3,4, M Stevens-Kroef5, M Lafage6, N Dastugue7, CJ Harrison8, F Mugneret9, K Bahloula1, S Struski10, MJ Gre´goire11, N Nadal12, E Lippert13, S Taviaux14, A Simons5, RP Kuiper5, AV Moorman8, K Barber15, A Bosly3, L Michaux4, P Vandenberghe4, I Lahortiga2,4, K De Keersmaecker2,4, I Wlodarska4, J Cools2,4, A Hagemeijer4,16 and HA Poirel1,16 on behalf of the GFCH (Groupe Francophone de Cytoge´ne´tique He´matologique) and the BCGHO (Belgian Cytogenetic Group for Hematology and Oncology) 1Hematologic Section of the Human Genetics Centre, Cliniques universitaires UCL Saint-Luc, Brussels, Belgium; 2Human Genetics - Department of Molecular and Developmental Genetics, VIB, Leuven, Belgium; 3Department of Hematology, Cliniques universitaires UCL de Mont-Godinne, Yvoir, Belgium; 4Centre for Human Genetics, University of Leuven, Leuven, Belgium; 5Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 6De´partement de Ge´ne´tique, CHU Timone, Marseille, France; 7Laboratoire d’He´matologie - Ge´ne´tique des He´mopathies, Hoˆpital Purpan, Toulouse, France; 8Leukemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK; 9Laboratoire de Cytoge´ne´tique, CHU Le Bocage, Dijon, France; 10Laboratoire d’He´matologie, Hoˆpital Haute Pierre, Strasbourg, France; 11Laboratoire de Ge´ne´tique, CHU de Nancy-Brabois, Vandoeuvre-Les-Nancy, France; 12Laboratoire d’He´matologie - Pavillon de Biologie, CHU Hoˆpital Nord, St Etienne, France; 13Laboratoire d’He´matologie, CHU de Bordeaux, Bordeaux, France; 14Laboratoire d’He´matologie – Ge´ne´tique mole´culaire et chromosomique, Hoˆpital Arnaud de Villeneuve, Montpellier, France and 15Leukemia Research Cytogenetics Group, Cancer Sciences Division, University of Southampton, Southampton, UK Episomes with the NUP214-ABL1 fusion gene have been Introduction 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 The translocation t(9;22)(q34;q11.2) fusing the ABL1 to the patients. An associated abnormality involving TLX1 or TLX3 BCR gene is the hallmark of chronic myeloid leukemia. The was found in all investigated cases. Fluorescent in situ molecular consequence of this translocation is the production of hybridization revealed a heterogeneous pattern of NUP214- a constitutively activated tyrosine kinase, BCR-ABL1, which is ABL1 amplification. Multiple episomes carrying the fusion were the target of therapy with the inhibitors of ABL1 kinase activity.1 detected in 24 patients. Episomes were observed in a The t(9;22) has also been observed in 3 and 25% of childhood significant number of nuclei in 18 cases, but in only 1–5% of and adult B-cell acute lymphoblastic leukemia, respectively, as nuclei in 6. In addition, intrachromosomal amplification (small 2–4 hsr) was identified either as the only change or in association well as rare cases of acute myeloid leukemia. with episomes in four cases and two T-ALL cell lines (PEER and Besides BCR, other ABL1 fusion partners have been rarely ALL-SIL). One case showed insertion of apparently non- described.5,6 The ETV6-ABL1 fusion of the translocation, amplified NUP214-ABL1 sequences at 14q12. The amplified t(9;12)(q34;p13), also revealed the same biological conse- sequences were analyzed using array-based CGH. quences including uncontrolled proliferation and increased These findings confirm that the NUP214-ABL1 gene requires 5 amplification for oncogenicity; it is part of a multistep process survival of hematopoietic progenitors. of leukemogenesis; and it can be a late event present only in In T-cell acute lymphoblastic leukemia (T-ALL), recent studies subpopulations. Data also provide in vivo evidence for a model have shown the presence of the NUP214-ABL1 fusion gene in of episome formation, amplification and optional reintegration 6% of cases, whereas BCR-ABL1 and ETV6-ABL1 are rare into the genome. Implications for the use of kinase inhibitors (o1%).5,7–9 The NUP214-ABL1 fusion gene was first reported are discussed. on amplified episomes due to extrachromosomal circularization Leukemia (2009) 23, 125–133; doi:10.1038/leu.2008.278; 9 published online 16 October 2008 of the 500 kb DNA fragment located between the two genes. Keywords: T-ALL; NUP214-ABL1; episomes; hsr; gene Intrachromosomal amplification of the fusion has been reported 10 amplification on chromosome 2 in one patient. More recently, the analysis of the breakpoints of a novel cryptic translocation t(9;14)(q34;q32) revealed an EML1-ABL1 fusion gene in a single case of T-ALL.11,12 Of interest, the NUP214-ABL1 and EML1-ABL1 fusions in T-ALL are usually associated with alterations of other genes such 9–12 Correspondence: Dr C Graux, Department of Hematology, Cliniques as CDKN2a, TLX1 or TLX3 and NOTCH1. These observations universitaires UCL de Mont-Godinne, Avenue Therasse 1, B-5530, indicate a multigene contribution to the pathogenesis of T-cell Yvoir, Belgium. leukemia. It has been postulated that (i) homo- or heterozygous E-mail: [email protected] deletion of the tumor suppressor gene CDKN2a impairs cell cycle The work was done at Centre for Human Genetics, University of control and favors genetic instability, (ii) activating NOTCH1 Leuven, Leuven, Belgium and Hematologic Section of the Genetics mutations provide T-cell precursors with self-renewal capacity, Centre, Cliniques universitaires UCL Saint-Luc, Brussels, Belgium. 16A Hagemeijer and HA Poirel are senior authors. (iii) ectopic expression of TLX1 or TLX3 impairs thymocyte Received 28 May 2008; revised 24 July 2008; accepted 29 August differentiation and (iv) constitutive kinase activity of ABL1 fusions 2008; published online 16 October 2008 provides proliferative and survival advantages.13 Amplification patterns of NUP214-ABL1 fusion gene C Graux et al 126 Given that tyrosine kinase inhibitors (TKI), such as imatinib, Fluorescence in situ hybridization suppress the constitutive kinase activity of ABL1, there is Each sample was tested with the LSI BCR/ABL1 dual color ES potential for their use in therapies of T-ALL patients with probe (Vysis, Ottignies, Belgium) either locally (38%) or NUP214-ABL1 and EML1-ABL1.9,11,14 centrally at the UCL in Brussels (62%). Cases with an abnormal Here, we report clinical and genetic characteristics of 27 hybridization pattern (more than 2 ABL1 signals per nucleus, T-ALL cases and genetics of two T-ALL cell lines positive for the asymmetry of the signals, aberrant localization of the signals on NUP214-ABL1 fusion gene. These data allow us to present a metaphase cells) were further characterized using BAC and model for NUP214-ABL1 fusion on episomes, followed by fosmid probes selected from http://www.ensemble.org (Chori optional re-integration in a chromosome as small amplified BACPAC Resources, Oakland, USA). These probes included sequences (homogeneously stained regions (hsr)). differentially labeled ABL1 break-apart BAC probes covering the 50 part and the 30 part of ABL1 (RP11-57C19 and RP11-83J21 clones, respectively). NUP214 break-apart fosmid probes (G248P89679D11 flanking the 50 part and G248P87560C9 Materials and methods flanking the 30 part of NUP214) were used to detect breakpoints on NUP214. BAC clone RP11-544A12 covering NUP214 was Patient samples used to assess its colocalization with ABL1. A set of probes Bone marrow, blood, lymph node or pleural fluid samples from targeting genes located at 9q34 (SET, GPR107, ASS, FUBP3, 347 T-ALL patients at diagnosis and, if possible, also at relapse LAMC3, NTNG2, VAV2) was used as described earlier to were collected from 21 centers in collaboration with the delimit 9q34 amplifications.9 TLX1/TLX3 rearrangement and ‘Groupe Francophone de Cytoge´ne´tique He´matologique’ and CDKN2a (p16) deletion screening was performed using com- the Belgian Cytogenetic Group for Hematology and Oncology. mercial probes (Dako, Glostrup, Denmark; Abbott, UK). A Eight T-ALL patients were included from the UK Cancer minimum of 200 nuclei were examined in each sample. When Cytogenetics Group (Patients 20–27 in Table 1). Although they an abnormality was present at a low percentage, 500 to 1000 were published earlier, they were not identified as NUP214- nuclei were examined. ABL1-positive; only the amplification of ABL1 was reported.8 Owing to the random selection, these patients were not used in assessing the frequency of the fusion in T-ALL. Reverse transcriptase PCR Samples were obtained according to the guidelines of Reverse transcriptase PCR (RT-PCR) for the NUP214-ABL1 the local ethical committees. Diagnosis of T-ALL was based fusion transcript and TLX1 or TLX3 expression was performed on morphology, cytochemistry and immunophenotyping in the different centers according to the local protocols. according to the World Health Organization and European NUP214-ABL1 positivity was centrally validated using semi- Group for the Immunological Characterization of Leukemias nested RT-PCR with the following primers in five cases: criteria.15,16 NUP214 ex23 F: 50-AGTCAGGCACCAGCTGTAAAC-30; NUP214 ex29 F: 50-AGGGAGGCTCTGTCTTTGGT-30; NUP214 ex31 F: 50-AGAGGGGGAGGTTTCCTCAGT-30; Cell lines NUP214 ex32 F: 50-GCCAAGACATTTGGTGGATT-30 combined ALL-SIL and PEER are T-ALL-derived cell lines positive for the with: NUP214-ABL1 fusion (DSMZ, Braunschweig, Germany). ALL- ABL1 ex3 R: 50-TAACTAAAGGTGAAAAGCTCCGG-30 (first SIL displays the following phenotype: CD2À, CD3À, cyCD3 þ , round) CD4 þ , CD5 þ , CD6 þ , CD7 þ , CD8 þ , CD13À, CD19À, and ABL1 ex2-3 R: 50-GTGAAGCCCAAACCAAAAAT-30 CD34À, TCRalpha/beta-, TCRgamma/delta- and karyotype: (second round). 90B95,XXYY,t(1;13)(p32;q32)x2, þ 6,del(6)(q25)x2, þ 8, þ 8,d- 0 17 Primers used for TLX1 expression: TLX1 ex2 F: 5 -GCGTCAAC el(9)(?p23p24)x2,t(10;14)(q24;q11.2)x2,add (p11)x2/90B95,sl, 0 17 AACCTCACTGGCC-3 ; -20,20.
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