t(4;10)(q12;p11)

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t(4;10)(q12;p11)

Clinics and Pathology

Disease Myeloproliferative syndrome with hypereosinophilia

Epidemiology Only one case to date, a 54-year old male patient.

Evolution Complete remission could not be obtained with hydroxyurea. Following the identification of the PDGFRA hybrid gene, imatinib was started, and the patient entered complete cytogenetic remission (CR). The patient is still in RT-PCR CR after 18 months

Genes involved and Proteins

Gene Name PDGFRA

Location 4q12

Protein Composed of an extracellular domain, a transmembrane domain, a juxtamembrane domain, and an intracellular domain; receptor tyrosine kinase; forms homodimer, and heterodimer with PDGFRB ; dimerization induces kinase domain activation, leading to the activation of intracellular signalling pathways (Kawagishi et al, 1995).

Somatic mutations Hybrid genes between various partners and PDFRGA occur in chronic myeloid leukaemia-like diseases with eosinophilia, mostly chronic eosinophilic leukemia (CEL), a clonal hypereosinophilic syndrome. PDGFRA partners known so far are: STRN (2p24) (Curtis et al, 2007), FIP1L1 (4q12) (Cools et al, 2003; Pardanani et al, 2004), CDK5RAP2 (9q33) (Walz et al, 2006), KIF5B (10p11) (Score et al, 2006), ETV6 (12p13) (Curtis et al, 2007), and BCR (22q11) (Baxter et al, 2002).
Mutations of platelet-derived growth factor receptor-alpha (PDGFRA) are observed in a subset of gastrointestinal stromal tumors (GISTs) (Heinrich et al, 2003).
Tumours with PDGFRA involvement are responsive to imatinib therapy (Cools et al, 2003; Debiec-Rychter et al, 2004).

Gene Name KIF5B

Location 10p11

Protein Composed of a N-terminal globular domain that hydrolyzes ATP and binds microtubule, a central alpha-helical coiled-coil domain (dimerization domain); and a C-terminal domain that interacts with other proteins, vesicles and membranous organelles. Kif5B is involved in microtubule-based polarized vesicular transport to the apical membrane in polarized axonal transport in neurons (Nakata and Hirokawa, 2003; Jacobson et al, 2007; Jaulin and Mostov, 2007). The role of the complex of syntaxin-1-syntabulin-KIF5B in axonal transport has been established (Cai et al, 2007). Kif5B and Kifc1 interact in motility and processing of early endocytic vesicles (Nath et al, 2007). KIF5B has been shown to be essential for axonal transport of mitochondria. KIF5B associates with the kinesin-binding domain (KBD) of RanBP2 to determines mitochondria localization (Cho et al, 2007). JNK forms a complex with KIF5B and ß-tubulin-III in neurites, and TNF disturbs axonal transport of mitochondria via JNK (Stagi et al, 2006).

Result of the chromosomal anomaly

Hybrid gene
Description In frame fusion of KIF5B exon 23 to PDGFRA exon 12; no reciprocal PDGFRA-KIF5B product

Fusion Protein
Description 156 kDa protein of 1372 amino acids; Composed of the N-terminal globular domain and the central alpha-helical coiled-coil domain (dimerization domain) of KIF5B, fused to the kinase domain of PDGFRA. It is likely that the dimerization domain induces constitutive activation of the kinase domain.

External links

Other database t(4;10)(q12;p11) Mitelman database (CGAP - NCBI)

Other database t(4;10)(q12;p11) CancerChromosomes (NCBI)

Other database	t(4;10)(q12;p11)	Mitelman database (CGAP - NCBI)
Other database	t(4;10)(q12;p11)	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

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Microtubules provide directional cues for polarized axonal transport through interaction with kinesin motor head.

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Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group.

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FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia.

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Identification of a novel imatinib responsive KIF5B-PDGFRA fusion gene following screening for PDGFRA overexpression in patients with hypereosinophilia.

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Unloading kinesin transported cargoes from the tubulin track via the inflammatory c-Jun N-terminal kinase pathway.

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Transient response to imatinib in a chronic eosinophilic leukemia associated with ins(9;4)(q33;q12q25) and a CDK5RAP2-PDGFRA fusion gene.

Walz C, Curtis C, Schnittger S, Schultheis B, Metzgeroth G, Schoch C, Lengfelder E, Erben P, Muller MC, Haferlach T, Hochhaus A, Hehlmann R, Cross NC, Reiter A.

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The FIP1L1-PDGFRA fusion gene cooperates with IL-5 to induce murine hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL)-like disease.

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Buitenhuis M, Verhagen LP, Cools J, Coffer PJ.

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Syntabulin-kinesin-1 family member 5B-mediated axonal transport contributes to activity-dependent presynaptic assembly.

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Association of the kinesin-binding domain of RanBP2 to KIF5B and KIF5C determines mitochondria localization and function.

Cho KI, Cai Y, Yi H, Yeh A, Aslanukov A, Ferreira PA.

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Two novel imatinib-responsive PDGFRA fusion genes in chronic eosinophilic leukaemia.

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Contributor(s)

Written 03-2008 Jean-Loup Huret

Jean Loup HURET, Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers, France

Citation

This paper should be referenced as such :
Huret JL . t(4;10)(q12;p11). Atlas Genet Cytogenet Oncol Haematol. March 2008 .
URL : http://AtlasGeneticsOncology.org/Genes/t0410q12p11ID1440.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Sat Dec 6 18:02:31 2008

Home Genes Leukemias Solid Tumours Cancer-Prone Deep Insight Case Reports Journals Portal Teaching

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.

Disease	Myeloproliferative syndrome with hypereosinophilia
Epidemiology	Only one case to date, a 54-year old male patient.
Evolution	Complete remission could not be obtained with hydroxyurea. Following the identification of the PDGFRA hybrid gene, imatinib was started, and the patient entered complete cytogenetic remission (CR). The patient is still in RT-PCR CR after 18 months

Gene Name	PDGFRA
Location	4q12
Protein	Composed of an extracellular domain, a transmembrane domain, a juxtamembrane domain, and an intracellular domain; receptor tyrosine kinase; forms homodimer, and heterodimer with PDGFRB ; dimerization induces kinase domain activation, leading to the activation of intracellular signalling pathways (Kawagishi et al, 1995).
Somatic mutations	Hybrid genes between various partners and PDFRGA occur in chronic myeloid leukaemia-like diseases with eosinophilia, mostly chronic eosinophilic leukemia (CEL), a clonal hypereosinophilic syndrome. PDGFRA partners known so far are: STRN (2p24) (Curtis et al, 2007), FIP1L1 (4q12) (Cools et al, 2003; Pardanani et al, 2004), CDK5RAP2 (9q33) (Walz et al, 2006), KIF5B (10p11) (Score et al, 2006), ETV6 (12p13) (Curtis et al, 2007), and BCR (22q11) (Baxter et al, 2002). Mutations of platelet-derived growth factor receptor-alpha (PDGFRA) are observed in a subset of gastrointestinal stromal tumors (GISTs) (Heinrich et al, 2003). Tumours with PDGFRA involvement are responsive to imatinib therapy (Cools et al, 2003; Debiec-Rychter et al, 2004).

Gene Name	KIF5B
Location	10p11
Protein	Composed of a N-terminal globular domain that hydrolyzes ATP and binds microtubule, a central alpha-helical coiled-coil domain (dimerization domain); and a C-terminal domain that interacts with other proteins, vesicles and membranous organelles. Kif5B is involved in microtubule-based polarized vesicular transport to the apical membrane in polarized axonal transport in neurons (Nakata and Hirokawa, 2003; Jacobson et al, 2007; Jaulin and Mostov, 2007). The role of the complex of syntaxin-1-syntabulin-KIF5B in axonal transport has been established (Cai et al, 2007). Kif5B and Kifc1 interact in motility and processing of early endocytic vesicles (Nath et al, 2007). KIF5B has been shown to be essential for axonal transport of mitochondria. KIF5B associates with the kinesin-binding domain (KBD) of RanBP2 to determines mitochondria localization (Cho et al, 2007). JNK forms a complex with KIF5B and ß-tubulin-III in neurites, and TNF disturbs axonal transport of mitochondria via JNK (Stagi et al, 2006).

Description	In frame fusion of KIF5B exon 23 to PDGFRA exon 12; no reciprocal PDGFRA-KIF5B product

Description	156 kDa protein of 1372 amino acids; Composed of the N-terminal globular domain and the central alpha-helical coiled-coil domain (dimerization domain) of KIF5B, fused to the kinase domain of PDGFRA. It is likely that the dimerization domain induces constitutive activation of the kinase domain.

Written	03-2008	Jean-Loup Huret
		Jean Loup HURET, Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers, France