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t(4;12)(q12;p13) PDGFRA::ETV6

Written2008-04Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

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ICD-Morpho 9975/3 Chronic myelogenous leukaemia, BCR-ABL1 positive; Myeloproliferative neoplasm, unclassifiable; Myelodysplastic/myeloproliferative neoplasm, unclassifiable
Atlas_Id 2137
Note See also the t(4;12)(q11-q21;p13) with CHIC2.and ETV6 involvements in M0 acute myeloid leukaemia (M0-AML), keeping in mind that a t(4:12)(q13-21;p12-13) has also been described in B-cell acute lymphocytic leukaemia (ALL) (GFCH, 1993; Behm et al., 1996; Elghezal et al., 2001), B-cell non Hodgkin's lymphoma (NHL) (Schouten et al., 1990; Palanisamy et al., 2002), and in a case of adult T-cell lymphoma/leukemia (Sadamori et al., 1991).

Clinics and Pathology

Disease Myeloproliferative disease with eosinophilia
Epidemiology Only one case to date, a 51 year old male patient.
Evolution The disease was rather indolent for over 7 years; imatinib was then started with significant resolution of symptoms, and the patient remains in cytogenetic remission 9 months later.

Genes involved and Proteins

Gene NamePDGFRA (platelet-derived growth factor receptor, alpha polypeptide)
Location 4q12
Protein Composed of an extracellular domain (the immunoglobulin-like motifs), a transmembrane domain, with an inhibitory juxtamembrane WW-like domain (Irusta et al., 2002), and an intracellular domain (kinase 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), herein described (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 NameETV6 (ets variant 6)
Location 12p13.2
Protein Contains a HLH domain and a ETS-DNA binding domain; ETS-related transcription regulator.

Result of the chromosomal anomaly

Hybrid gene
Transcript 5' ETV6-3' PDGFRA; Fusion between ETV6 intron 6 and PDGFRA intron 11; reciprocal product not found -> in frame fusion between ETV6 exon 6 and PDGFRA exon 12.
Fusion Protein
Description The N-term ETV6- C-term PDGFRA fusion protein retains most of ETV6, including the pointed domain and the ETS domain, fused to the WW-like domain and the kinase domain of PDGFRA; altough the WW-like domain is thought to act as an autoinhibitory element preventing kinase over-activation.


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
Rearrangement of the MLL gene confers a poor prognosis in childhood acute lymphoblastic leukemia, regardless of presenting age.
Behm FG, Raimondi SC, Frestedt JL, Liu Q, Crist WM, Downing JR, Rivera GK, Kersey JH, Pui CH.
Blood. 1996 Apr 1;87(7):2870-7.
PMID 8639906
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
Reassessment of childhood B-lineage lymphoblastic leukemia karyotypes using spectral analysis.
Elghezal H, Le Guyader G, Radford-Weiss I, Perot C, Van Den Akker J, Eydoux P, Vekemans M, Romana SP.
Genes Chromosomes Cancer. 2001 Apr;30(4):383-92.
PMID 11241791
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
Definition of an inhibitory juxtamembrane WW-like domain in the platelet-derived growth factor beta receptor.
Irusta PM, Luo Y, Bakht O, Lai CC, Smith SO, DiMaio D.
J Biol Chem. 2002 Oct 11;277(41):38627-34. Epub 2002 Aug 13.
PMID 12181311
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
Collaborative study of karyotypes in childhood acute lymphoblastic leukemias. Groupe Français de Cytogenetique Hematologique.
No authors listed
Leukemia. 1993 Jan;7(1):10-9.
PMID 8418369
Similar patterns of genomic alterations characterize primary mediastinal large-B-cell lymphoma and diffuse large-B-cell lymphoma.
Palanisamy N, Abou-Elella AA, Chaganti SR, Houldsworth J, Offit K, Louie DC, Terayu-Feldstein J, Cigudosa JC, Rao PH, Sanger WG, Weisenburger DD, Chaganti RS.
Genes Chromosomes Cancer. 2002 Feb;33(2):114-22.
PMID 11793437
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
Relationship between chromosomal breakpoint and molecular rearrangement of T-cell antigen receptors in adult T-cell leukaemia.
Sadamori N, Isobe M, Shimizu S, Yamamori T, Itoyama T, Ikeda S, Yamada Y, Ichimaru M.
Acta Haematol. 1991;86(1):14-9.
PMID 1659101
Abnormalities involving chromosome 6 in newly diagnosed patients with non-Hodgkin's lymphoma. Nebraska Lymphoma Study Group.
Schouten HC, Sanger WG, Weisenburger DD, Armitage JO.
Cancer Genet Cytogenet. 1990 Jul 1;47(1):73-82.
PMID 2357689
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
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


This paper should be referenced as such :
Huret, JL
t(4;12)(q12;p13) PDGFRA/ETV6
Atlas Genet Cytogenet Oncol Haematol. 2009;13(4):302-303.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other genes implicated (Data extracted from papers in the Atlas) [ 2 ]


Translocations implicated (Data extracted from papers in the Atlas)

 t(4;12)(q12;p13) PDGFRA/ETV6

External links

Mitelman databaset(4;12)(q12;p13)
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9975/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed

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