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NUP214::ABL1 fusion gene on amplified episomes

Written2012-06Nathalie Nadal
Laboratoire d'hematologie, Pavillon de Biologie, CHU Hopital Nord, 42055 St Etienne Cedex 2, France
This article is an update of :
2005-09Nathalie Nadal
Laboratoire d'hematologie, Pavillon de Biologie, CHU Hopital Nord, 42055 St Etienne Cedex 2, France

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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.


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 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 NameABL1 (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 NameNUP214 (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

Hybrid gene
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.
Fusion Protein
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.


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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 :
History of this paper:
Nadal, N. Amplified NUP214/ABL1. Atlas Genet Cytogenet Oncol Haematol. 2006;10(2):107-109.

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