t(5;14)(q33;q24)

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t(5;14)(q33;q24)

Identity

G-band analysis. Partial karyotype showing the t(5;14)(q33;q24).

Clinics and Pathology

Disease CML-like myeloproliferative disorder.

Note L Atypical CML.

Epidemiology Very rare, only one case described.

Clinics Eosinophilia, basophilia, psoriasic skin lesions, splenomegaly.

Treatment Imatinib mesylate after 14 years from diagnosis.

Evolution Molecular remission after one year of treatment.

Prognosis Good.

Cytogenetics

FISH analyses :
(A) FISH using cosmids 9-4 (green) and 4-1 (red) showing the putative involvement of PDGFRB in the translocation.
(B) FISH using BACs RPCI-11 286O18 (red, centromeric to NIN) and RPCI-11 248J18 (covering almost all NIN) showing a split between them compatible with the molecular breakpoint found.
(C) FISH painting using STAR*FISH human whole chromosome specific probes for chromosomes 5 (Cy3, red) and 14 (FITC, green) which confirms the translocation between them.

Additional anomalies Sole anomaly.

Variants No variants described.

Genes involved and Proteins

Gene Name NIN

Location 14q22.1

Note This gene is involved only in this translocation.

Dna / Rna 31 exons spanning 111.3 Kb on 14q22.1. Transcription is from telomere to centromere. 4-5 alternative transcripts.

Protein Homooligomer. Interacts with GSK3B (GSK3-beta) via its C-terminus domain, ait also interacts with C14ORF166 preventing its phosphorylation by GSK3-beta. NIN is a component of the core centrosome. Arranged in a tubular conformation with an open and a closed end within the centrosome. In the mother centrosome, it localizes at both ends of the centrosome tube, including the site of centrosome duplication, while in the daughter centrosome it is present only at the closed end. Requires PCM1 for centrosome localization. In interphase cells, it is localized in the centrosome. Decreases in metaphase and anaphase and reappears in telophase. Its expression is ubiquitous and is high in heart and skeletal muscle.

Gene Name PDGFRB

Dna / Rna 23 exons spanning 42 Kb on 5q32. Transcription is from telomere to centromere. 1 transcript with 5.6 Kb.

Protein This gene encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. These growth factors are mitogens for cells of mesenchymal origin. The identity of the growth factor bound to a receptor monomer determines whether the functional receptor is a homodimer or a heterodimer, composed of both platelet-derived growth factor receptor alpha and beta polypeptides. This gene is flanked on chromosome 5 by the genes for granulocyte-macrophage colony-stimulating factor ( GM-CSF ) and macrophage-colony stimulating factor receptor; all three genes may be implicated in the 5q- syndrome. Several rare translocations between this gene and other partners result in chronic eosinophilic leukemia, atypical CML or chronic myelomonocitic leukemia with eosinophilia. Only one case with a t(5;14)(q31;p12) and CEV14-PDGFRB fusion has been found as a secondary event in a patient with relapsed acute myeloid leukemia.

Result of the chromosomal anomaly

Hybrid gene
Description Fusion in-frame between NIN exon 28 and PDGFRB exon 12.

Transcript 5' NIN-PDGFRB 3'

Detection See Ref 2 below. PDGFRB-NIN was also detected.

Fusion Protein

Schematic representation of the fusion NIN-PDGFRB consequence of the t(5;14)(q33;q24) in a chronic myeloproliferative disorder with eosinophilia. From up to down: PDGFRB, NIN and the putative chimeric NIN-PDGFRB structure. TM, transmembrane domain; TK, tyrosine kinase domain; LZ, leuzine-zipper domain. Coiled coil domains on NIN and NIN-PDGFRB are indicated with asterisks.

Description The fusion gene is predicted to encode a NIN-PDGFRB protein of 300 kDA (2595 aminoacids) retaining most of NIN protein (2047 of the wild-type 2116 aminoacids) and most of the intracellular domain of PDGFRB (548 aminoacids), including the entire tyrosine kinase domain. This fusion involves PDGFRB exon 12, whereas all other reported PDGFRB fusions involve exon 11. Consequently, NIN-PDGFRB lacks the PDGFRB transmembrane domain. From ninein, the fusion would retain the potential GTP-binding site, a large coiled-coil domain, four leucine-zipper domains and a GSK-3B binding site.

Oncogenesis NIN shares features in common with other tyrosine kinase fusion partners, namely widespread expression and the presence of putative oligomerization domains. Although there is no direct experimental proof, it is likely that the NIN promoter drives expression of the chimeric gene in hemopoietic progenitor cells, and the oligomerization domain(s) result in ligand-independent activation of the PDGFRB kinase moiety by mimicking the normal process of ligand-induced receptor dimerization.

External links

Other database t(5;14)(q33;q24) Mitelman database (CGAP - NCBI)

Other database t(5;14)(q33;q24) CancerChromosomes (NCBI)

Other database	t(5;14)(q33;q24)	Mitelman database (CGAP - NCBI)
Other database	t(5;14)(q33;q24)	CancerChromosomes (NCBI)

Bibliography

Novel translocations that disrupt the platelet-derived growth factor receptor beta (PDGFRB) gene in BCR-ABL-negative chronic myeloproliferative disorders.

Baxter EJ, Kulkarni S, Vizmanos JL, Jaju R, Martinelli G, Testoni N, Hughes G, Salamanchuk Z, Calasanz MJ, Lahortiga I, Pocock CF, Dang R, Fidler C, Wainscoat JS, Boultwood J, Cross NC

British journal of haematology. 2003 ; 120 (2) : 251-256.

PMID 12542482

NIN, a gene encoding a CEP110-like centrosomal protein, is fused to PDGFRB in a patient with a t(5;14)(q33;q24) and an imatinib-responsive myeloproliferative disorder.

Vizmanos JL, Novo FJ, Romˆ°n JP, Baxter EJ, Lahortiga I, Larrˆ°yoz MJ, Odero MD, Giraldo P, Calasanz MJ, Cross NC

Cancer research. 2004 ; 64 (8) : 2673-2676.

PMID 15087377

Contributor(s)

Written 09-2004 JosÈ Luis Vizmanos

Citation

This paper should be referenced as such :
Vizmanos JL . t(5;14)(q33;q24). Atlas Genet Cytogenet Oncol Haematol. Septem ber 2004 .
URL : http://AtlasGeneticsOncology.org/Genes/t0514q33q24ID1325.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Mon Jul 14 16:33:05 2008

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For comments and suggestions or contributions, please contact us

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

Disease	CML-like myeloproliferative disorder.
Note	L Atypical CML.
Epidemiology	Very rare, only one case described.
Clinics	Eosinophilia, basophilia, psoriasic skin lesions, splenomegaly.
Treatment	Imatinib mesylate after 14 years from diagnosis.
Evolution	Molecular remission after one year of treatment.
Prognosis	Good.



	FISH analyses : (A) FISH using cosmids 9-4 (green) and 4-1 (red) showing the putative involvement of PDGFRB in the translocation. (B) FISH using BACs RPCI-11 286O18 (red, centromeric to NIN) and RPCI-11 248J18 (covering almost all NIN) showing a split between them compatible with the molecular breakpoint found. (C) FISH painting using STAR*FISH human whole chromosome specific probes for chromosomes 5 (Cy3, red) and 14 (FITC, green) which confirms the translocation between them.

Additional anomalies	Sole anomaly.
Variants	No variants described.

Gene Name	NIN
Location	14q22.1
Note	This gene is involved only in this translocation.
Dna / Rna	31 exons spanning 111.3 Kb on 14q22.1. Transcription is from telomere to centromere. 4-5 alternative transcripts.
Protein	Homooligomer. Interacts with GSK3B (GSK3-beta) via its C-terminus domain, ait also interacts with C14ORF166 preventing its phosphorylation by GSK3-beta. NIN is a component of the core centrosome. Arranged in a tubular conformation with an open and a closed end within the centrosome. In the mother centrosome, it localizes at both ends of the centrosome tube, including the site of centrosome duplication, while in the daughter centrosome it is present only at the closed end. Requires PCM1 for centrosome localization. In interphase cells, it is localized in the centrosome. Decreases in metaphase and anaphase and reappears in telophase. Its expression is ubiquitous and is high in heart and skeletal muscle.

Gene Name	PDGFRB
Dna / Rna	23 exons spanning 42 Kb on 5q32. Transcription is from telomere to centromere. 1 transcript with 5.6 Kb.
Protein	This gene encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. These growth factors are mitogens for cells of mesenchymal origin. The identity of the growth factor bound to a receptor monomer determines whether the functional receptor is a homodimer or a heterodimer, composed of both platelet-derived growth factor receptor alpha and beta polypeptides. This gene is flanked on chromosome 5 by the genes for granulocyte-macrophage colony-stimulating factor ( GM-CSF ) and macrophage-colony stimulating factor receptor; all three genes may be implicated in the 5q- syndrome. Several rare translocations between this gene and other partners result in chronic eosinophilic leukemia, atypical CML or chronic myelomonocitic leukemia with eosinophilia. Only one case with a t(5;14)(q31;p12) and CEV14-PDGFRB fusion has been found as a secondary event in a patient with relapsed acute myeloid leukemia.

Description	Fusion in-frame between NIN exon 28 and PDGFRB exon 12.
Transcript	5' NIN-PDGFRB 3'
Detection	See Ref 2 below. PDGFRB-NIN was also detected.



	Schematic representation of the fusion NIN-PDGFRB consequence of the t(5;14)(q33;q24) in a chronic myeloproliferative disorder with eosinophilia. From up to down: PDGFRB, NIN and the putative chimeric NIN-PDGFRB structure. TM, transmembrane domain; TK, tyrosine kinase domain; LZ, leuzine-zipper domain. Coiled coil domains on NIN and NIN-PDGFRB are indicated with asterisks.

Description	The fusion gene is predicted to encode a NIN-PDGFRB protein of 300 kDA (2595 aminoacids) retaining most of NIN protein (2047 of the wild-type 2116 aminoacids) and most of the intracellular domain of PDGFRB (548 aminoacids), including the entire tyrosine kinase domain. This fusion involves PDGFRB exon 12, whereas all other reported PDGFRB fusions involve exon 11. Consequently, NIN-PDGFRB lacks the PDGFRB transmembrane domain. From ninein, the fusion would retain the potential GTP-binding site, a large coiled-coil domain, four leucine-zipper domains and a GSK-3B binding site.
Oncogenesis	NIN shares features in common with other tyrosine kinase fusion partners, namely widespread expression and the presence of putative oligomerization domains. Although there is no direct experimental proof, it is likely that the NIN promoter drives expression of the chimeric gene in hemopoietic progenitor cells, and the oligomerization domain(s) result in ligand-independent activation of the PDGFRB kinase moiety by mimicking the normal process of ligand-induced receptor dimerization.