t(4;10)(q12;p11) KIF5B/PDGFRA
2008-03-01 Jean-Loup Huret Affiliation1.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
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 (platelet-derived growth factor receptor, alpha polypeptide)
Location
4q12
Protein description
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).
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 (kinesin family member 5B)
Location
10p11.22
Protein description
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
Description
In frame fusion of KIF5B exon 23 to PDGFRA exon 12; no reciprocal PDGFRA-KIF5B product156 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.
Highly cited references
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 16498388 | 2006 | Identification of a novel imatinib responsive KIF5B-PDGFRA fusion gene following screening for PDGFRA overexpression in patients with hypereosinophilia. | 0 |
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 12023981 | 2002 | The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA. | Baxter EJ et al |
| 17440089 | 2007 | Molecular mechanisms underlying FIP1L1-PDGFRA-mediated myeloproliferation. | Buitenhuis M et al |
| 17611281 | 2007 | Syntabulin-kinesin-1 family member 5B-mediated axonal transport contributes to activity-dependent presynaptic assembly. | Cai Q et al |
| 17887960 | 2007 | Association of the kinesin-binding domain of RanBP2 to KIF5B and KIF5C determines mitochondria localization and function. | Cho KI et al |
| 12660384 | 2003 | A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. | Cools J et al |
| 17555450 | 2007 | Two novel imatinib-responsive PDGFRA fusion genes in chronic eosinophilic leukaemia. | Curtis CE et al |
| 15010069 | 2004 | 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. | Debiec-Rychter M et al |
| 12191989 | 2002 | The motor protein kinesin-1 links neurofibromin and merlin in a common cellular pathway of neurofibromatosis. | Hakimi MA et al |
| 12522257 | 2003 | PDGFRA activating mutations in gastrointestinal stromal tumors. | Heinrich MC et al |
| 11969417 | 2002 | Phosphorylation-dependent interaction of kinesin light chain 2 and the 14-3-3 protein. | Ichimura T et al |
| 17925219 | 2007 | Catch the KIF5B train to the apical surface. | Jacobson C et al |
| 17925227 | 2007 | Polarization-dependent selective transport to the apical membrane by KIF5B in MDCK cells. | Jaulin F et al |
| 8586421 | 1995 | Structure, organization, and transcription units of the human alpha-platelet-derived growth factor receptor gene, PDGFRA. | Kawagishi J et al |
| 12191015 | 2002 | Identification of RanBP2- and kinesin-mediated transport pathways with restricted neuronal and subcellular localization. | Mavlyutov TA et al |
| 12975348 | 2003 | Microtubules provide directional cues for polarized axonal transport through interaction with kinesin motor head. | Nakata T et al |
| 17360972 | 2007 | Kif5B and Kifc1 interact and are required for motility and fission of early endocytic vesicles in mouse liver. | Nath S et al |
| 15284118 | 2004 | FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. | Pardanani A et al |
| 16498388 | 2006 | Identification of a novel imatinib responsive KIF5B-PDGFRA fusion gene following screening for PDGFRA overexpression in patients with hypereosinophilia. | Score J et al |
| 17068110 | 2006 | Unloading kinesin transported cargoes from the tubulin track via the inflammatory c-Jun N-terminal kinase pathway. | Stagi M et al |
| 16845659 | 2006 | Transient response to imatinib in a chronic eosinophilic leukemia associated with ins(9;4)(q33;q12q25) and a CDK5RAP2-PDGFRA fusion gene. | Walz C et al |
| 16418325 | 2006 | The FIP1L1-PDGFRA fusion gene cooperates with IL-5 to induce murine hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL)-like disease. | Yamada Y et al |
Summary
Fusion gene
KIF5B/PDGFRA KIF5B (10p11.22) PDGFRA (4q12) M t(4;10)(q12;p11)|KIF5B/PDGFRA KIF5B (10p11.22) PDGFRA (4q12) TIC
Citation
Jean-Loup Huret
t(4;10)(q12;p11) KIF5B/PDGFRA
Atlas Genet Cytogenet Oncol Haematol. 2008-03-01
Online version: http://atlasgeneticsoncology.org/haematological/1440/t(4
