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t(4;10)(q12;p11) KIF5B/PDGFRA

Written2008-03Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9965/3 Myeloid and lymphoid neoplasms with PDGFRA rearrangement
ICD-Morpho 9975/3 Chronic myelogenous leukaemia, BCR-ABL1 positive; Myeloproliferative neoplasm, unclassifiable; Myelodysplastic/myeloproliferative neoplasm, unclassifiable
Atlas_Id 1440

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 NamePDGFRA (platelet-derived growth factor receptor, alpha polypeptide)
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 NameKIF5B (kinesin family member 5B)
Location 10p11.22
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.
  

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

The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA.
Baxter EJ, Hochhaus A, Bolufer P, Reiter A, Fernandez JM, Senent L, Cervera J, Moscardo F, Sanz MA, Cross NC.
Hum Mol Genet. 2002 Jun 1;11(12):1391-7.
PMID 12023981
 
Molecular mechanisms underlying FIP1L1-PDGFRA-mediated myeloproliferation.
Buitenhuis M, Verhagen LP, Cools J, Coffer PJ.
Cancer Res. 2007 Apr 15;67(8):3759-66.
PMID 17440089
 
Syntabulin-kinesin-1 family member 5B-mediated axonal transport contributes to activity-dependent presynaptic assembly.
Cai Q, Pan PY, Sheng ZH.
J Neurosci. 2007 Jul 4;27(27):7284-96.
PMID 17611281
 
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.
Traffic. 2007 Dec;8(12):1722-35.
PMID 17887960
 
A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome.
Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, Kutok J, Clark J, Galinsky I, Griffin JD, Cross NC, Tefferi A, Malone J, Alam R, Schrier SL, Schmid J, Rose M, Vandenberghe P, Verhoef G, Boogaerts M, Wlodarska I, Kantarjian H, Marynen P, Coutre SE, Stone R, Gilliland DG.
N Engl J Med. 2003 Mar 27;348(13):1201-14.
PMID 12660384
 
Two novel imatinib-responsive PDGFRA fusion genes in chronic eosinophilic leukaemia.
Curtis CE, Grand FH, Musto P, Clark A, Murphy J, Perla G, Minervini MM, Stewart J, Reiter A, Cross NC.
Br J Haematol. 2007 Jul;138(1):77-81.
PMID 17555450
 
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, Dumez H, Judson I, Wasag B, Verweij J, Brown M, Dimitrijevic S, Sciot R, Stul M, Vranck H, Scurr M, Hagemeijer A, van Glabbeke M, van Oosterom AT; EORTC Soft Tissue and Bone Sarcoma Group.
Eur J Cancer. 2004 Mar;40(5):689-95.
PMID 15010069
 
The motor protein kinesin-1 links neurofibromin and merlin in a common cellular pathway of neurofibromatosis.
Hakimi MA, Speicher DW, Shiekhattar R.
J Biol Chem. 2002 Oct 4;277(40):36909-12.
PMID 12191989
 
PDGFRA activating mutations in gastrointestinal stromal tumors.
Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, Singer S, Griffith DJ, Haley A, Town A, Demetri GD, Fletcher CD, Fletcher JA.
Science. 2003 Jan 31;299(5607):708-10.
PMID 12522257
 
Phosphorylation-dependent interaction of kinesin light chain 2 and the 14-3-3 protein.
Ichimura T, Wakamiya-Tsuruta A, Itagaki C, Taoka M, Hayano T, Natsume T, Isobe T.
Biochemistry. 2002 Apr 30;41(17):5566-72.
PMID 11969417
 
Catch the KIF5B train to the apical surface.
Jacobson C, Mostov K.
Dev Cell. 2007 Oct;13(4):457-8.
PMID 17925219
 
Polarization-dependent selective transport to the apical membrane by KIF5B in MDCK cells.
Jaulin F, Xue X, Rodriguez-Boulan E, Kreitzer G.
Dev Cell. 2007 Oct;13(4):511-22.
PMID 17925227
 
Structure, organization, and transcription units of the human alpha-platelet-derived growth factor receptor gene, PDGFRA.
Kawagishi J, Kumabe T, Yoshimoto T, Yamamoto T.
Genomics. 1995 Nov 20;30(2):224-32.
PMID 8586421
 
Identification of RanBP2- and kinesin-mediated transport pathways with restricted neuronal and subcellular localization.
Mavlyutov TA, Cai Y, Ferreira PA.
Traffic. 2002 Sep;3(9):630-40.
PMID 12191015
 
Microtubules provide directional cues for polarized axonal transport through interaction with kinesin motor head.
Nakata T, Hirokawa N.
J Cell Biol. 2003 Sep 15;162(6):1045-55.
PMID 12975348
 
Kif5B and Kifc1 interact and are required for motility and fission of early endocytic vesicles in mouse liver.
Nath S, Bananis E, Sarkar S, Stockert RJ, Sperry AO, Murray JW, Wolkoff AW.
Mol Biol Cell. 2007 May;18(5):1839-49.
PMID 17360972
 
FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia.
Pardanani A, Brockman SR, Paternoster SF, Flynn HC, Ketterling RP, Lasho TL, Ho CL, Li CY, Dewald GW, Tefferi A.
Blood. 2004 Nov 15;104(10):3038-45.
PMID 15284118
 
Identification of a novel imatinib responsive KIF5B-PDGFRA fusion gene following screening for PDGFRA overexpression in patients with hypereosinophilia.
Score J, Curtis C, Waghorn K, Stalder M, Jotterand M, Grand FH, Cross NC.
Leukemia. 2006 May;20(5):827-32.
PMID 16498388
 
Unloading kinesin transported cargoes from the tubulin track via the inflammatory c-Jun N-terminal kinase pathway.
Stagi M, Gorlovoy P, Larionov S, Takahashi K, Neumann H.
FASEB J. 2006 Dec;20(14):2573-5.
PMID 17068110
 
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.
Genes Chromosomes Cancer. 2006 Oct;45(10):950-6.
PMID 16845659
 
The FIP1L1-PDGFRA fusion gene cooperates with IL-5 to induce murine hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL)-like disease.
Yamada Y, Rothenberg ME, Lee AW, Akei HS, Brandt EB, Williams DA, Cancelas JA.
Blood. 2006 May 15;107(10):4071-9.
PMID 16418325
 

Citation

This paper should be referenced as such :
Huret, JL
t(4;10)(q12;p11)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(3):237-238.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Anomalies/t0410q12p11ID1440.html


Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]

Genes PDGFRA

Translocations implicated (Data extracted from papers in the Atlas)

 t(4;10)(q12;p11) KIF5B/PDGFRA

External links

KIF5B (10p11.22) PDGFRA (4q12)

KIF5B (10p11.22) PDGFRA (4q12)

Mitelman databaset(4;10)(q12;p11) [Case List]    t(4;10)(q12;p11) [Association List] Mitelman database (CGAP - NCBI)
arrayMapTopo ( C42) Morph ( 9965/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9975/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
Mitelman databaseKIF5B/PDGFRA [MCList]  KIF5B (10p11.22) PDGFRA (4q12)
TICdbKIF5B/PDGFRA  KIF5B (10p11.22) PDGFRA (4q12)
 
Disease databaset(4;10)(q12;p11) KIF5B/PDGFRA
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
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jlhuret@AtlasGeneticsOncology.org.