| Written | 2012-06 | Nathalie Nadal |
| Laboratoire d'hematologie, Pavillon de Biologie, CHU Hopital Nord, 42055 St Etienne Cedex 2, France |
| This article is an update of : |
| 2005-09 | Nathalie Nadal | |
| Laboratoire d'hematologie, Pavillon de Biologie, CHU Hopital Nord, 42055 St Etienne Cedex 2, France |
| Identity |
| ICD-Topo | C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS |
| ICD-Morpho | 9837/3 T lymphoblastic leukaemia/lymphoma |
| Atlas_Id | 1397 |
| Note | Episomes are submicroscopic extrachromosomal structures. |
 | |
| Episomal amplification of ABL detected by FISH with the commercial probe LSI BCR-ABL ES. | |
| Clinics and Pathology |
| Disease | T-cell acute lymphoblastic leukemia (T-ALL) |
| Note | Not seen in B-cell ALL or other malignant diseases. |
| Phenotype / cell stem origin | Immature T-cell leukemia (CD3+, CD2+ and CD7+). |
| Epidemiology | In about 5% of T-ALL. Mainly observed in T-ALL associated with the mutually exclusive overexpression of the oncogenes HOX11 and HOX11L2. Found in pediatric and adults T-ALL. |
| Clinics | No major clinical differences between NUP214-ABL negative and positive T-ALL. |
| Cytology | Lymphoblasts. |
| Treatment | NUP214-ABL1 cells are sensitive to tyrosine kinase inhibitors (ITK). Targeting therapies may improve outcome of patients with T-ALL expressing NUP214-ABL1 but the clinical experience is, yet, too limited to conclude. |
| Prognosis | Most data, but not all, suggests that NUP214-ABL1 fusion gene amplification in T-ALL is associated with poor outcome. |
| Genetics |
| Mechanism of gene amplification The main hypothesis is that genomic amplification is a dynamic process. Molecular chronology of genomic amplification has been schematically described as follows. The first step is the production of submicroscopic, acentric, circular, extrachromosomal DNA molecules which replicate autonomously, called episomes. These DNA molecules are made of amplified genes. 2 mechanisms for the formation of episomes have been proposed: Conservative which preserves the original DNA sequence at the native chromosomal locus and non conservative which leads to the deletion of the original sequence at the native locus. The second step corresponds to an increase in copy number resulting from unequal mitotic segregation and an increase in size. They enlarge over time to form progressively heterogeneously sized structures, microscopically visible, called double minutes (dmin). In a later step they may integrate into chromosomes to generate intrachromosomally amplified structures (HSR). In some cases dmins or HSRs may form directly without precursors. |
| Cytogenetics |
| Cytogenetics Morphological | Not detectable by conventional cytogenetics. Cryptic, no dmin. |
| Cytogenetics Molecular | FISH using commercially available ABL1 probe shows multiple extrachromosomal sites on metaphases and multiple signals in interphase nuclei. The extrachromosomal amplification of ABL1 appears to be pathognomonique for the presence of NUP214-ABL1 fusion in T-ALL.There may be a corresponding deletion of the ABL1 probe on one of the chromosomes 9 (see note above concerning mechanisms of gene amplification). |
| Probes | ABL1 probe. |
| Additional anomalies | None. In apparently normal karyotype or with variable additional abnormalities. |
| Genes involved and Proteins |
| Gene Name | ABL1 (v-abl Abelson murine leukemia viral oncogene homolog 1) |
| Location | 9q34.12 |
| Dna / Rna | Alternate splicing. mRNA of 6 and 7 kb. |
| Protein | Protein 145 kDa; Localization: nuclear and cytoplasmic; Tyrosine kinase; Ubiquitously expressed. ABL1 modulates T-cell development and plays a role in cytoskeletal remodelling processes in T-cells. |
| Gene Name | NUP214 (nucleoporin 214kDa) |
| Location | 9q34.13 |
| Note | More telomeric than ABL1. |
| Dna / Rna | Other names: CAN, CAIN, Nucleoporin. 7.5 kb mRNA. |
| Protein | Component of the Nuclear Pore Complex. 214 kDa; 2 dimerization domains (2 leucine zippers) and a repeated motif; forms homodimers. Mediate nucleocytoplasmic transport. Localisation: nuclear membrane; cytoplasmic face. |
| Result of the chromosomal anomaly |
| Note | NUP214 is recognized as being the second most prevalent fusion gene involving ABL1. |
| Description | Molecular analyses delineated the amplicon as a 500 kb region from chromosome band 9q34 containing the genes ABL1, LAMC3 and NUP214. The genomic region from ABL1 to NUP214 circularizes to generate the NUP214-ABL1 fusion gene = New mechanism for generation of a fusion gene. The breakpoint within ABL1 occurs in intron 1 in most cases, in intron 2 in other cases (coincides with ABL1 breakpoint in the Philadelphia chromosome). Whilst the breakpoint in NUP214 is variable (ranging from intron 23 to intron 34). |
| Transcript | NUP214-ABL1 fusion gene. |
| Detection | RT-PCR of the fusion transcript. |
| Description | The NUP214-ABL transcript encodes a 239-333 kDa protein which includes the coiled-coil domain (dimerisation motifs necessary for tyrosine kinase activation and neoplastic transformation) of NUP214 and the tyrosine kinase domain of ABL1. NUP214-ABL protein is a constitutively activated tyrosine kinase most likely implicated in the pathogenesis of T-ALL in a similar mechanism of action as for BCR-ABL as it activates similar pathways and for its sensitivity to ITK. However NUP214-ABL protein is less potent and requires amplification for neoplastic transformation. |
| Oncogenesis | NUP214 is also involved in the translocation t(6;9) seen in myeloid malignancies which results in the fusion gene DEK-NUP214. Unlike NUP214-ABL where the N-terminal region of NUP214 is retained, in DEK-NUP214, it is the C-terminal region of NUP214 which is present. The mode of leukemogenesis of DEK-NUP214 is thought to be interference with nucleocytoplasmic transport processes. It is unknown whether NUP214-ABL acts in the same way. |
| Bibliography |
| NUP214-ABL1 amplification in t(5;14)/HOX11L2-positive ALL present with several forms and may have a prognostic significance. |
| Ballerini P, Busson M, Fasola S, van den Akker J, Lapillonne H, Romana SP, Marynen P, Bernard OA, Landman-Parker J, Berger R. |
| Leukemia. 2005 Mar;19(3):468-70. |
| PMID 15674415 |
| Amplification of the ABL gene in T-cell acute lymphoblastic leukemia. |
| Barber KE, Martineau M, Harewood L, Stewart M, Cameron E, Strefford JC, Rutherford S, Allen TD, Broadfield ZJ, Cheung KL, Harris RL, Jalali GR, Moorman AV, Robinson HM, Harrison CJ. |
| Leukemia. 2004 Jun;18(6):1153-6. |
| PMID 15057249 |
| NUP214-ABL1 in adult T-ALL: the GMALL study group experience. |
| Burmeister T, Gokbuget N, Reinhardt R, Rieder H, Hoelzer D, Schwartz S. |
| Blood. 2006 Nov 15;108(10):3556-9. Epub 2006 Jul 27. |
| PMID 16873673 |
| ABL1 fusion genes in hematological malignancies: a review. |
| De Braekeleer E, Douet-Guilbert N, Rowe D, Bown N, Morel F, Berthou C, Ferec C, De Braekeleer M. |
| Eur J Haematol. 2011 May;86(5):361-71. doi: 10.1111/j.1600-0609.2011.01586.x. Epub 2011 Mar 23. (REVIEW) |
| PMID 21435002 |
| Fusion of EML1 to ABL1 in T-cell acute lymphoblastic leukemia with cryptic t(9;14)(q34;q32). |
| De Keersmaecker K, Graux C, Odero MD, Mentens N, Somers R, Maertens J, Wlodarska I, Vandenberghe P, Hagemeijer A, Marynen P, Cools J. |
| Blood. 2005 Jun 15;105(12):4849-52. Epub 2005 Feb 15. |
| PMID 15713800 |
| Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. |
| Graux C, Cools J, Melotte C, Quentmeier H, Ferrando A, Levine R, Vermeesch JR, Stul M, Dutta B, Boeckx N, Bosly A, Heimann P, Uyttebroeck A, Mentens N, Somers R, MacLeod RA, Drexler HG, Look AT, Gilliland DG, Michaux L, Vandenberghe P, Wlodarska I, Marynen P, Hagemeijer A. |
| Nat Genet. 2004 Oct;36(10):1084-9. Epub 2004 Sep 12. |
| PMID 15361874 |
| Activity of tyrosine kinase inhibitors against human NUP214-ABL1-positive T cell malignancies. |
| Quintas-Cardama A, Tong W, Manshouri T, Vega F, Lennon PA, Cools J, Gilliland DG, Lee F, Cortes J, Kantarjian H, Garcia-Manero G. |
| Leukemia. 2008 Jun;22(6):1117-24. Epub 2008 Apr 10. |
| PMID 18401417 |
| Fusion of NUP214 to ABL1 on amplified episomes in T-ALL--implications for treatment. |
| Stergianou K, Fox C, Russell NH. |
| Leukemia. 2005 Sep;19(9):1680-1. |
| PMID 16015385 |
| The importance of circular DNA in mammalian gene amplification. |
| Wahl GM. |
| Cancer Res. 1989 Mar 15;49(6):1333-40. (REVIEW) |
| PMID 2647287 |
| Citation |
| This paper should be referenced as such : |
| Nadal, N |
| NUP214/ABL1 fusion gene on amplified episomes |
| Atlas Genet Cytogenet Oncol Haematol. 2012;16(12):921-923. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Anomalies/ampNUP214ABL1ID1397.html |
| History of this paper: |
| Nadal, N. Amplified NUP214/ABL1. Atlas Genet Cytogenet Oncol Haematol. 2006;10(2):107-109. |
| http://documents.irevues.inist.fr/bitstream/handle/2042/38298/09-2005-ampNUP214ABL1ID1397.pdf |
| External links |
| arrayMap (UZH-SIB Zurich) | Topo ( C42) Morph ( 9837/3) - [auto + random 100 samples .. if exist ] [tabulated segments] |
| REVIEW articles | automatic search in PubMed |
| Last year articles | automatic search in PubMed |
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