amplified NUP214/ABL1

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amplified NUP214/ABL1

Identity

Other names NUP214/ABL1 fusion gene on amplified episomes

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)

Phenotype / cell stem origin Immature T-cell leukemia (CD3+, CD2+ and CD7+). Not seen in B-cell ALL.

Epidemiology In about 6% of T-ALL. Mainly observed in T-ALL associated with the mutually exclusive overexpression of the oncogenes HOX11 and HOX11L2. Found in pediatric T-ALL and adults T-ALL.

Cytology lymphoblasts

Prognosis Present data suggests that NUP214-ABL1 fusion gene amplification in T-ALL is associated with poor outcome. NUP214-ABL1 is sensitive to the tyrosine kinase inhibitor imatinib mesylate. Targeting therapies may improve outcome.

Cytogenetics

Note Mechanism of gene amplification
The main hypothesis for genomic amplification mechanism is that it 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 Cryptic extrachromosomal amplification of the fusion NUP214-ABL. Rearrangement invisible by conventional cytogenetics. No dmins observed.

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 below concerning mechanisms of gene amplification).

Additional anomalies Associated with an apparently normal karyotype with banding techniques or variable additional abnormalities.

Genes involved and Proteins

Gene Name ABL1

Location 9q34.1

Dna / Rna Alternate splicing. mRNA of 6 and 7 kb

Protein 145 kDa; Localization: nuclear and cytoplasmic; Tyrosine kinase; Ubiquitously expressed

Gene Name NUP214 (nuclear pore complex protein 241 kDa) or CAN, CAIN, Nucleoporin

Location 9q34.3, more telomeric than ABL1.

Dna / Rna 7.5 kb mRNA

Protein 214 kDa; dimerization domains (2 leucine zippers) and a repeated motif; forms homodimers. Nuclear membrane localisation. Component of the Nuclear Pore Complex. Mediate nucleocytoplasmic transport.

Result of the chromosomal anomaly

Hybrid gene
Description Molecular analysis 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 intron1 (coincides with ABL1 breakpoint in the Philadelphia chromosome). Whilst the breakpoint in NUP214 is variable (ranging from intron 23 to intron 34).

Detection RT-PCR

Fusion Protein
Description The NUP214-ABL transcript encodes a 239-333 kDa protein. NUP214-ABL retains the N-terminal region of NUP 214 which includes the predicted coiled-coil domains that serve as oligomerisation motifs. NUP214-ABL contains SH3, SH2 and kinase domains of ABL1. NUP214-ABL is a constitutively activated tyrosine kinase that activates similar pathways as BCR_ABL1.

Bibliography

The importance of circular DNA in mammalian gene amplification.

Wahl GM

Cancer research. 1989 ; 49 (6) : 1333-1340.

PMID 2647287

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 : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2004 ; 18 (6) : 1153-1156.

PMID 15057249

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

Nature genetics. 2004 ; 36 (10) : 1084-1089.

PMID 15361874

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 : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2005 ; 19 (3) : 468-470.

PMID 15674415

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 ; 105 (12) : 4849-4852.

PMID 15713800

Fusion of NUP214 to ABL1 on amplified episomes in T-ALL--implications for treatment.

Stergianou K, Fox C, Russell NH

Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2005 ; 19 (9) : 1680-1681.

PMID 16015385

Contributor(s)

Written 09-2005 Nathalie Nadal

Laboratoire d'hématologie (niveau 1), Pavillon de Biologie, CHU Hôpital Nord, 42055 St Etienne Cedex 2, France

Citation

This paper should be referenced as such :
Nadal N . amplified NUP214/ABL1. Atlas Genet Cytogenet Oncol Haematol. Septem ber 2005 .
URL : http://AtlasGeneticsOncology.org/Genes/ampNUP214ABL1ID1397.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Wed Sep 24 21:05:47 2008

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For comments and suggestions or contributions, please contact us

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Other names	NUP214/ABL1 fusion gene on amplified episomes


	Episomal amplification of ABL detected by FISH with the commercial probe LSI BCR-ABL ES.

Disease	T-cell acute lymphoblastic leukemia (T-ALL)
Phenotype / cell stem origin	Immature T-cell leukemia (CD3+, CD2+ and CD7+). Not seen in B-cell ALL.
Epidemiology	In about 6% of T-ALL. Mainly observed in T-ALL associated with the mutually exclusive overexpression of the oncogenes HOX11 and HOX11L2. Found in pediatric T-ALL and adults T-ALL.
Cytology	lymphoblasts
Prognosis	Present data suggests that NUP214-ABL1 fusion gene amplification in T-ALL is associated with poor outcome. NUP214-ABL1 is sensitive to the tyrosine kinase inhibitor imatinib mesylate. Targeting therapies may improve outcome.

Note	Mechanism of gene amplification The main hypothesis for genomic amplification mechanism is that it 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	Cryptic extrachromosomal amplification of the fusion NUP214-ABL. Rearrangement invisible by conventional cytogenetics. No dmins observed.
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 below concerning mechanisms of gene amplification).
Additional anomalies	Associated with an apparently normal karyotype with banding techniques or variable additional abnormalities.

Gene Name	ABL1
Location	9q34.1
Dna / Rna	Alternate splicing. mRNA of 6 and 7 kb
Protein	145 kDa; Localization: nuclear and cytoplasmic; Tyrosine kinase; Ubiquitously expressed

Gene Name	NUP214 (nuclear pore complex protein 241 kDa) or CAN, CAIN, Nucleoporin
Location	9q34.3, more telomeric than ABL1.
Dna / Rna	7.5 kb mRNA
Protein	214 kDa; dimerization domains (2 leucine zippers) and a repeated motif; forms homodimers. Nuclear membrane localisation. Component of the Nuclear Pore Complex. Mediate nucleocytoplasmic transport.

Description	Molecular analysis 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 intron1 (coincides with ABL1 breakpoint in the Philadelphia chromosome). Whilst the breakpoint in NUP214 is variable (ranging from intron 23 to intron 34).
Detection	RT-PCR

Description	The NUP214-ABL transcript encodes a 239-333 kDa protein. NUP214-ABL retains the N-terminal region of NUP 214 which includes the predicted coiled-coil domains that serve as oligomerisation motifs. NUP214-ABL contains SH3, SH2 and kinase domains of ABL1. NUP214-ABL is a constitutively activated tyrosine kinase that activates similar pathways as BCR_ABL1.

Written	09-2005	Nathalie Nadal
		Laboratoire d'hématologie (niveau 1), Pavillon de Biologie, CHU Hôpital Nord, 42055 St Etienne Cedex 2, France