t(10;11)(q25;p15)

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t(10;11)(q25;p15)

Identity

G-band analysis. Partial karyotype showing the t(10;11)(q25;p15). Courtesy I Lahortiga, María J Calasanz and María D Odero. Department of Genetics, University of Navarra, Spain.

Clinics and Pathology

Disease T-cell acute lymphoblastic leukemia with biphenotipic characteristics (T/myeloid).

Epidemiology Very rare, only one case described.

Clinics Adenopathies, moderate splenomegaly. Two different morphological populations detected by flow cytometry.

Treatment Hematological and cytogenetic remission after induction therapy(Ara-C, Idarubicin, VP-16). Postremission therapy (two courses of Ida-Ara-C and mitoxantrone-Ara-C). Autologous transplantation. Relapse and exitus.

Evolution Relapse and exitus.

Prognosis Bad.

Cytogenetics

FISH analyses. Left BAC RPCI-11 348A20 (red, covering NUP98) shows a split compatible with the molecular breakpoint found; RPCI-11 555F1 (green, 500 Kb telomeric to NUP98) labels normal chromosome 11 and der(10). Right BAC RPCI-11 252O7 (green, covering ADD3) shows a split compatible with the molecular breakpoint found; RPCI-11 348A20 shows the split in NUP98. Courtesy I Lahortiga, María J Calasanz and María D Odero. Department of Genetics, University of Navarra, Spain.

Additional anomalies sole anomaly

Variants no variants described

Genes involved and Proteins

Gene Name ADD3

Location 10q25.1-q25.2

Note This gene is involved only in this translocation.

Dna / Rna 15 exons spanning 129.52 Kb on 10q25.1-10q25.2. Transcription is from centromere to telomere. 2-3 alternative transcripts.

Protein Is membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network and binds to calmodulin. Adducins are heteromeric proteins composed of different subunits referred to as adducin alpha, beta and gamma encoded by distinct genes and belong to a family of membrane skeletal proteins involved in the assembly of spectrin-actin network in erythrocytes and at sites of cell-cell contact in epithelial tissues. Structurally, each subunit is comprised of two distinct domains. The amino-terminal region is protease resistant and globular in shape, while the carboxy-terminal region is protease sensitive. The latter contains multiple phosphorylation sites for protein kinase C, the binding site for calmodulin, and is required for association with spectrin and actin. Alternatively spliced adducin gamma transcripts encoding different isoforms have been described. The functions of the different isoforms are not known.

Gene Name NUP98

Location 11p15

Dna / Rna 33 exons spanning 122.54 Kb on 11p15. Transcription is from centromere to telomere. 3-4 alternative transcripts.

Protein Nup98 and Nup96 play a role in the bidirectional transport across the nucleoporin complex (NPC). The repeat domain in Nup98 has a direct role in the transport. Signal-mediated nuclear import and export proceed through the nuclear pore complex (NPC), which is comprised of approximately 50 unique proteins collectively known as nucleoporins. The 98 kD nucleoporin is generated through a biogenesis pathway that involves synthesis and proteolytic cleavage of a 186 kD precursor protein. This cleavage results in the 98 kD nucleoporin as well as a 96 kD nucleoporin, both of which are localized to the nucleoplasmic side of the NPC. The human gene has been shown to fuse to several genes following chromosome translocatons in acute myelogenous leukemia (AML) and T-cell acute lymphocytic leukemia (T-ALL). This gene is one of several genes located in the imprinted gene domain of 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with the Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocortical carcinoma, and lung, ovarian, and breast cancer. Alternative splicing of this gene results in several transcript variants; however, not all variants have been fully described.

Result of the chromosomal anomaly

Hybrid gene
Description Fusion in-frame between NUP98 exon 10 and ADD3 exon 13 (transcript variant 1) and between NUP98 exon 10 and ADD3 exon 14 (transcript variant 2)r

Transcript 5' NUP98-ADD3 3'

Detection ADD3-NUP98 was also detected at a lower level.

Fusion Protein

Schematic representation of the fusion NUP98-ADD3 consecuence of the t(10;11)(q25;p15) in a T-cell acute lymphoblastic leukemia with biphenotipic characteristics. From up to down: ADD3, NUP98 and the putative chimeric NUP98-ADD3 structure. FG-repeats, phenilalanine-glycine repeats; bipartite NLS, bipartite nuclear localization signal. Coiled coil domains on ADD3 and NUP98-ADD3 are indicated with asterisks.

Description The fusion gene is predicted to encode a NUP98-ADD3 protein of 566-598 aminoacids retaining the N-terminal FG repeat motif of NUP98 and the C-terminal phosphorilation sites and the calmodulin binding region of ADD3.

Oncogenesis In all the NUP98 fusions reported the FG-repeats are retained. In the NUP98 rearrangements involving the HOX family, the 3' region of these genes with the homodomain are retained so the fusion protein could act as an oncogenic transcription factor. In NUP98 fusions with non-HOX genes the partners have regions with a significant probability of adopting a coiled-coil conformation. In all cases the coiled-coil domain are retained in the chimeric protein. This domain could promote the oligomerization of the fusion protein activating its oncogenic potential.

External links

Other database t(10;11)(q25;p15) Mitelman database (CGAP - NCBI)

Other database t(10;11)(q25;p15) CancerChromosomes (NCBI)

Other database	t(10;11)(q25;p15)	Mitelman database (CGAP - NCBI)
Other database	t(10;11)(q25;p15)	CancerChromosomes (NCBI)

To be noted

Additional cases are needed to delineate the epidemiology of this rare entity:
you are welcome to submit a paper to our new Case Report section.

Bibliography

NUP98 is fused to adducin 3 in a patient with T-cell acute lymphoblastic leukemia and myeloid markers, with a new translocation t(10;11)(q25;p15).

Lahortiga I, Vizmanos JL, Agirre X, Vˆ°zquez I, Cigudosa JC, Larrayoz MJ, Sala F, Gorosquieta A, Perez-Equiza K, Calasanz MJ, Odero MD

Cancer research. 2003 ; 63 (12) : 3079-3083.

PMID 12810632

Contributor(s)

Written 03-2005 José Luis Vizmanos

Citation

This paper should be referenced as such :
Vizmanos JL . t(10;11)(q25;p15). Atlas Genet Cytogenet Oncol Haematol. March 2005 .
URL : http://AtlasGeneticsOncology.org/Genes/t1011q25p15ID1285.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Mon Aug 11 21:20:43 2008

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For comments and suggestions or contributions, please contact us

j.l.huret@chu-poitiers.fr.

Disease	T-cell acute lymphoblastic leukemia with biphenotipic characteristics (T/myeloid).
Epidemiology	Very rare, only one case described.
Clinics	Adenopathies, moderate splenomegaly. Two different morphological populations detected by flow cytometry.
Treatment	Hematological and cytogenetic remission after induction therapy(Ara-C, Idarubicin, VP-16). Postremission therapy (two courses of Ida-Ara-C and mitoxantrone-Ara-C). Autologous transplantation. Relapse and exitus.
Evolution	Relapse and exitus.
Prognosis	Bad.



	FISH analyses. Left BAC RPCI-11 348A20 (red, covering NUP98) shows a split compatible with the molecular breakpoint found; RPCI-11 555F1 (green, 500 Kb telomeric to NUP98) labels normal chromosome 11 and der(10). Right BAC RPCI-11 252O7 (green, covering ADD3) shows a split compatible with the molecular breakpoint found; RPCI-11 348A20 shows the split in NUP98. Courtesy I Lahortiga, María J Calasanz and María D Odero. Department of Genetics, University of Navarra, Spain.

Additional anomalies	sole anomaly
Variants	no variants described

Gene Name	ADD3
Location	10q25.1-q25.2
Note	This gene is involved only in this translocation.
Dna / Rna	15 exons spanning 129.52 Kb on 10q25.1-10q25.2. Transcription is from centromere to telomere. 2-3 alternative transcripts.
Protein	Is membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network and binds to calmodulin. Adducins are heteromeric proteins composed of different subunits referred to as adducin alpha, beta and gamma encoded by distinct genes and belong to a family of membrane skeletal proteins involved in the assembly of spectrin-actin network in erythrocytes and at sites of cell-cell contact in epithelial tissues. Structurally, each subunit is comprised of two distinct domains. The amino-terminal region is protease resistant and globular in shape, while the carboxy-terminal region is protease sensitive. The latter contains multiple phosphorylation sites for protein kinase C, the binding site for calmodulin, and is required for association with spectrin and actin. Alternatively spliced adducin gamma transcripts encoding different isoforms have been described. The functions of the different isoforms are not known.

Gene Name	NUP98
Location	11p15
Dna / Rna	33 exons spanning 122.54 Kb on 11p15. Transcription is from centromere to telomere. 3-4 alternative transcripts.
Protein	Nup98 and Nup96 play a role in the bidirectional transport across the nucleoporin complex (NPC). The repeat domain in Nup98 has a direct role in the transport. Signal-mediated nuclear import and export proceed through the nuclear pore complex (NPC), which is comprised of approximately 50 unique proteins collectively known as nucleoporins. The 98 kD nucleoporin is generated through a biogenesis pathway that involves synthesis and proteolytic cleavage of a 186 kD precursor protein. This cleavage results in the 98 kD nucleoporin as well as a 96 kD nucleoporin, both of which are localized to the nucleoplasmic side of the NPC. The human gene has been shown to fuse to several genes following chromosome translocatons in acute myelogenous leukemia (AML) and T-cell acute lymphocytic leukemia (T-ALL). This gene is one of several genes located in the imprinted gene domain of 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with the Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocortical carcinoma, and lung, ovarian, and breast cancer. Alternative splicing of this gene results in several transcript variants; however, not all variants have been fully described.

Description	Fusion in-frame between NUP98 exon 10 and ADD3 exon 13 (transcript variant 1) and between NUP98 exon 10 and ADD3 exon 14 (transcript variant 2)r
Transcript	5' NUP98-ADD3 3'
Detection	ADD3-NUP98 was also detected at a lower level.



	Schematic representation of the fusion NUP98-ADD3 consecuence of the t(10;11)(q25;p15) in a T-cell acute lymphoblastic leukemia with biphenotipic characteristics. From up to down: ADD3, NUP98 and the putative chimeric NUP98-ADD3 structure. FG-repeats, phenilalanine-glycine repeats; bipartite NLS, bipartite nuclear localization signal. Coiled coil domains on ADD3 and NUP98-ADD3 are indicated with asterisks.

Description	The fusion gene is predicted to encode a NUP98-ADD3 protein of 566-598 aminoacids retaining the N-terminal FG repeat motif of NUP98 and the C-terminal phosphorilation sites and the calmodulin binding region of ADD3.
Oncogenesis	In all the NUP98 fusions reported the FG-repeats are retained. In the NUP98 rearrangements involving the HOX family, the 3' region of these genes with the homodomain are retained so the fusion protein could act as an oncogenic transcription factor. In NUP98 fusions with non-HOX genes the partners have regions with a significant probability of adopting a coiled-coil conformation. In all cases the coiled-coil domain are retained in the chimeric protein. This domain could promote the oligomerization of the fusion protein activating its oncogenic potential.