t(5;11)(q35;p15.5)

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t(5;11)(q35;p15.5)

Clinics and Pathology

Disease de novo acute non lymphocytic leukemia (ANLL)

Phenotype / cell stem origin No specific subtype. Only 5 cases reported to date (1 ANLL-M1, 2 ANLL-M2, 2 ANLL-M4)

Epidemiology all 5 reported cases were children or young adults (age range 3-18 years). Male: female ratio 1.5:1

Cytogenetics

Cytogenetics Morphological The t(5;11)(q35;p15.5) is not detectable by G-banding. Three cases were reported as cryptic t(5;11) associated with del(5q); a further two cases were identified in apparently normal karyotypes.

Cytogenetics Molecular In one FISH study using whole chromosome paints, three out of four cases of childhood ANLL with del(5q) as the sole cytogenetic abnormality were found to have a cryptic t(5;11). In a second study using chromosome-specific subtelomeric probes, two out of 31 children and young adults (19 years) with a normal G-banded karyotype were found to have a cryptic t(5;11).
Note: While the der(11) is detectable by single colour painting using chromosome 5 whole chromosome paint (WCP), the der(5) is not detectable using chromosome 11 WCP. Neither M-FISH or SKY can reliably detect the t(5;11).

Fig 1. Identification of a cryptic t(5;11) using the M-TEL assay. Bone marrow metaphase from a normal karyotype ANLL child hybridized with the M-TEL1 probe set. Chromosomes 1, 3, 7, 9, 13, 15, 17, 19, 21 and X and Y probes were all correctly hybridized. However, one homologue of chromosome 5 has chromosome 11 material on the q arm (yellow), and the corresponding chromosome 11 homologue has chromosome 5 material on the p arm (green). This corresponds to a balanced translocation, t(5q;11p). The der(5) and der(11) are indicated by arrows.

Probes Subtelomeric probes: PAC GS-240-G13 (5q), PAC GS-908-H22 (11p), both from Incyte Genomics NSD1 BAC: CTC HSP 2301A4 (available from Incyte Genomics); NUP98: PAC1173 K1, p9R1 (exons 10-12 of NUP98 gene), p6G2 (exons 13-14 of NUP98 gene)

Genes involved and Proteins

Gene Name NUP98

Location 11p15.5

Note at least 8 different fusion partners for NUP98 in leukaemia

Dna / Rna Two major transcripts: 4.0 and 7.0 kb. The 4.0 kb transcript consists of 20 exons.

Protein 98 kD protein. Component of the nuclear pore complex, which regulates nucleocytoplasmic transport of protein and RNA. Contains multiple phenylalanine-glycine (FG) repeats which act as Œdocking' sites for transport receptors.

Gene Name NSD1 (nuclear receptor-binding, SET domain-containing protein 1)

Location 5q35

Dna / Rna at least 21 exons, cDNA is 8552 bp, open reading frame of 8088 bp

Protein predicted protein of 2696 amino acids. Contains at least 6 functional domains: su(var)3-9, enhancer-of-zeste, trithorax (SET), proline-tryptophan-tryptophan-proline (PWWP-I, PWWP-II), plant homeodomain proteinfinger domains (PHD-I, PHD-II, PHD-III) and ten putative nuclear localization signals.

Result of the chromosomal anomaly

Hybrid gene
Note reciprocal NSD1-NUP98 fusion also present in all cases tested

Description The NUP98 and NSD1 mRNA are fused in-frame joining nucleotides 1552 of NUP98 to nucleotide 3506 of NSD1. The reciprocal transcript fuses NSD1 and NUP98 mRNA in-frame joining nucleotide 3505 of NSD1 to nucleotide 1553 of NUP98.

Detection RT-PCR with sense NUP98-5 (5'-TCTTGGTACAGGAGCCTTTG-3', and antisense NSD1-1 (5'TCCAAAAGCCACTTGCTTGGC-3') primers

Fusion Protein

Fig 2. Schematic representation of the NUP98-NSD1 fusion protein. The wild type NUP98 and NSD1 proteins are also shown. The putative NUP98-NSD1 fusion protein would retain the NH2 terminal region of NUP98 containing the phenylalanine-glycine (FG) repeat domains and the COOH terminal region of NSD1 containing the SET, SET domain associated cysteine-rich (SAC) and PHD finger domains.

External links

Other database t(5;11)(q35;p15.5) Mitelman database (CGAP - NCBI)

Other database t(5;11)(q35;p15.5) CancerChromosomes (NCBI)

Other database	t(5;11)(q35;p15.5)	Mitelman database (CGAP - NCBI)
Other database	t(5;11)(q35;p15.5)	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

Two distinct nuclear receptor interaction domains in NSD1, a novel SET protein that exhibits characteristics of both corepressors and coactivators.

Huang N, vom Baur E, Garnier JM, Lerouge T, Vonesch JL, Lutz Y, Chambon P, Losson R

The EMBO journal. 1998 ; 17 (12) : 3398-3412.

PMID 9628876

An optimized set of human telomere clones for studying telomere integrity and architecture.

Knight SJ, Lese CM, Precht KS, Kuc J, Ning Y, Lucas S, Regan R, Brenan M, Nicod A, Lawrie NM, Cardy DL, Nguyen H, Hudson TJ, Riethman HC, Ledbetter DH, Flint J

American journal of human genetics. 2000 ; 67 (2) : 320-332.

PMID 10869233

A new recurrent translocation, t(5;11)(q35;p15.5), associated with del(5q) in childhood acute myeloid leukemia. The UK Cancer Cytogenetics Group (UKCCG)

Jaju RJ, Haas OA, Neat M, Harbott J, Saha V, Boultwood J, Brown JM, Pirc-Danoewinata H, Krings BW, Mˆºller U, Morris SW, Wainscoat JS, Kearney L

Blood. 1999 ; 94 (2) : 773-780.

PMID 10397745

Potential role for DNA topoisomerase II poisons in the generation of t(11;20)(p15;q11) translocations.

Ahuja HG, Felix CA, Aplan PD

Genes, chromosomes & cancer. 2000 ; 29 (2) : 96-105.

PMID 10959088

A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute myeloid leukemia.

Jaju RJ, Fidler C, Haas OA, Strickson AJ, Watkins F, Clark K, Cross NC, Cheng JF, Aplan PD, Kearney L, Boultwood J, Wainscoat JS

Blood. 2001 ; 98 (4) : 1264-1267.

PMID 11493482

Subtelomeric chromosome rearrangements are detected using an innovative 12-color FISH assay (M-TEL).

Brown J, Saracoglu K, Uhrig S, Speicher MR, Eils R, Kearney L

Nature medicine. 2001 ; 7 (4) : 497-501.

PMID 11283680

Molecular characterization of NSD1, a human homologue of the mouse Nsd1 gene.

Kurotaki N, Harada N, Yoshiura K, Sugano S, Niikawa N, Matsumoto N

Gene. 2001 ; 279 (2) : 197-204.

PMID 11733144

NUP98 gene fusions in hematologic malignancies.

Lam DH, Aplan PD

Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2001 ; 15 (11) : 1689-1695.

PMID 11681408

A cryptic t(5;11)(q35;p15.5) in 2 children with acute myeloid leukemia with apparently normal karyotypes, identified by a multiplex fluorescence in situ hybridization telomere assay.

Brown J, Jawad M, Twigg SR, Saracoglu K, Sauerbrey A, Thomas AE, Eils R, Harbott J, Kearney L

Blood. 2002 ; 99 (7) : 2526-2531.

PMID 11895789

Contributor(s)

Written 03-2002 Lyndal Kearney

Citation

This paper should be referenced as such :
Kearney L . t(5;11)(q35;p15.5). Atlas Genet Cytogenet Oncol Haematol. March 2002 .
URL : http://AtlasGeneticsOncology.org/Genes/t0511q35p15ID1209.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Mon Jul 14 16:33:04 2008

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Disease	de novo acute non lymphocytic leukemia (ANLL)
Phenotype / cell stem origin	No specific subtype. Only 5 cases reported to date (1 ANLL-M1, 2 ANLL-M2, 2 ANLL-M4)
Epidemiology	all 5 reported cases were children or young adults (age range 3-18 years). Male: female ratio 1.5:1

Cytogenetics Morphological	The t(5;11)(q35;p15.5) is not detectable by G-banding. Three cases were reported as cryptic t(5;11) associated with del(5q); a further two cases were identified in apparently normal karyotypes.
Cytogenetics Molecular	In one FISH study using whole chromosome paints, three out of four cases of childhood ANLL with del(5q) as the sole cytogenetic abnormality were found to have a cryptic t(5;11). In a second study using chromosome-specific subtelomeric probes, two out of 31 children and young adults (19 years) with a normal G-banded karyotype were found to have a cryptic t(5;11). Note: While the der(11) is detectable by single colour painting using chromosome 5 whole chromosome paint (WCP), the der(5) is not detectable using chromosome 11 WCP. Neither M-FISH or SKY can reliably detect the t(5;11).


	Fig 1. Identification of a cryptic t(5;11) using the M-TEL assay. Bone marrow metaphase from a normal karyotype ANLL child hybridized with the M-TEL1 probe set. Chromosomes 1, 3, 7, 9, 13, 15, 17, 19, 21 and X and Y probes were all correctly hybridized. However, one homologue of chromosome 5 has chromosome 11 material on the q arm (yellow), and the corresponding chromosome 11 homologue has chromosome 5 material on the p arm (green). This corresponds to a balanced translocation, t(5q;11p). The der(5) and der(11) are indicated by arrows.

Probes	Subtelomeric probes: PAC GS-240-G13 (5q), PAC GS-908-H22 (11p), both from Incyte Genomics NSD1 BAC: CTC HSP 2301A4 (available from Incyte Genomics); NUP98: PAC1173 K1, p9R1 (exons 10-12 of NUP98 gene), p6G2 (exons 13-14 of NUP98 gene)

Gene Name	NUP98
Location	11p15.5
Note	at least 8 different fusion partners for NUP98 in leukaemia
Dna / Rna	Two major transcripts: 4.0 and 7.0 kb. The 4.0 kb transcript consists of 20 exons.
Protein	98 kD protein. Component of the nuclear pore complex, which regulates nucleocytoplasmic transport of protein and RNA. Contains multiple phenylalanine-glycine (FG) repeats which act as Œdocking' sites for transport receptors.

Gene Name	NSD1 (nuclear receptor-binding, SET domain-containing protein 1)
Location	5q35
Dna / Rna	at least 21 exons, cDNA is 8552 bp, open reading frame of 8088 bp
Protein	predicted protein of 2696 amino acids. Contains at least 6 functional domains: su(var)3-9, enhancer-of-zeste, trithorax (SET), proline-tryptophan-tryptophan-proline (PWWP-I, PWWP-II), plant homeodomain proteinfinger domains (PHD-I, PHD-II, PHD-III) and ten putative nuclear localization signals.

Note	reciprocal NSD1-NUP98 fusion also present in all cases tested
Description	The NUP98 and NSD1 mRNA are fused in-frame joining nucleotides 1552 of NUP98 to nucleotide 3506 of NSD1. The reciprocal transcript fuses NSD1 and NUP98 mRNA in-frame joining nucleotide 3505 of NSD1 to nucleotide 1553 of NUP98.
Detection	RT-PCR with sense NUP98-5 (5'-TCTTGGTACAGGAGCCTTTG-3', and antisense NSD1-1 (5'TCCAAAAGCCACTTGCTTGGC-3') primers



	Fig 2. Schematic representation of the NUP98-NSD1 fusion protein. The wild type NUP98 and NSD1 proteins are also shown. The putative NUP98-NSD1 fusion protein would retain the NH2 terminal region of NUP98 containing the phenylalanine-glycine (FG) repeat domains and the COOH terminal region of NSD1 containing the SET, SET domain associated cysteine-rich (SAC) and PHD finger domains.