t(2;4)(p22;q12)

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t(2;4)(p22;q12)

Clinics and Pathology

Disease Myeloproliferative disease with eosinophilia

Epidemiology Only one case to date, a 64 year old male patient.

Prognosis The patient remained in complete remission for 24 months of treatment with imatinib, but refused any more treatment, althoughthere was no side effect. Elevated eosinophil counts were again detected 14 months after end of treatment.

Genes involved and Proteins

Gene Name STRN

Location 2p22.2

Protein Composed of a caveolin-binding domain, a coiled-coil domain, a calmodulin-binding domain, and at least 6 WD-repeats. Striatin (STRN) binds many proteins, and forms multi-protein complexes. It is a scaffolding protein; striatin contains a caveolin-binding consensus motif, and binds caveolin-1, the major protein involved in caveolae and lipid rafts. Striatin is also involved in signaling and trafficking in a Ca²⁺ dependant manner, exhibiting a dual role in endocytic process and signaling.

Gene Name PDGFRA

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), herein described (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).

Result of the chromosomal anomaly

Hybrid gene
Transcript 5' STRN-3' PDGFRA; Fusion between STRN intron 6 and a truncated PDGFRA exon 12; reciprocal product not found -> in frame fusion between STRN exon 6 and PDGFRA exon 12.

Fusion Protein
Description The N-term STRN - C-term PDGFRA fusion protein retains the caveolin-binding domain, the coiled-coil domain, and the calmodulin-binding domain, but not the WD-repeats of STRN, fused to a truncated WW-like domain and the kinase domain of PDGFRA; the coiled-coil domain from STRN may act as a dimerization motif that could constitutively activate PDGFRA tyrosine kinase.

External links

Other database t(2;4)(p22;q12) Mitelman database (CGAP - NCBI)

Other database t(2;4)(p22;q12) CancerChromosomes (NCBI)

Other database	t(2;4)(p22;q12)	Mitelman database (CGAP - NCBI)
Other database	t(2;4)(p22;q12)	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

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 peptide and protein ligands for the caveolin-scaffolding domain. Implications for the interaction of caveolin with caveolae-associated proteins.

Couet J, Li S, Okamoto T, Ikezu T, Lisanti MP.

J Biol Chem. 1997 Mar 7;272(10):6525-33.

PMID 9045678

Striatin, a calmodulin-dependent scaffolding protein, directly binds caveolin-1.

Gaillard S, Bartoli M, Castets F, Monneron A.

FEBS Lett. 2001 Nov 9;508(1):49-52.

PMID 11707266

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

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

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

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

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

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

The striatin family: a new signaling platform in dendritic spines.

Benoist M, Gaillard S, Castets F.

J Physiol Paris. 2006 Mar-May;99(2-3):146-53. Epub 2006 Feb 7. (Review)

PMID 16460920

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

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

Contributor(s)

Written 05-2008 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(2;4)(p22;q12). Atlas Genet Cytogenet Oncol Haematol. May 2008 .
URL : http://AtlasGeneticsOncology.org/Genes/t0204p22q12ID2136.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Wed Sep 24 21:06:22 2008

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

For comments and suggestions or contributions, please contact us

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

Disease	Myeloproliferative disease with eosinophilia
Epidemiology	Only one case to date, a 64 year old male patient.
Prognosis	The patient remained in complete remission for 24 months of treatment with imatinib, but refused any more treatment, althoughthere was no side effect. Elevated eosinophil counts were again detected 14 months after end of treatment.

Gene Name	STRN
Location	2p22.2
Protein	Composed of a caveolin-binding domain, a coiled-coil domain, a calmodulin-binding domain, and at least 6 WD-repeats. Striatin (STRN) binds many proteins, and forms multi-protein complexes. It is a scaffolding protein; striatin contains a caveolin-binding consensus motif, and binds caveolin-1, the major protein involved in caveolae and lipid rafts. Striatin is also involved in signaling and trafficking in a Ca²⁺ dependant manner, exhibiting a dual role in endocytic process and signaling.

Gene Name	PDGFRA
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), herein described (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).

Transcript	5' STRN-3' PDGFRA; Fusion between STRN intron 6 and a truncated PDGFRA exon 12; reciprocal product not found -> in frame fusion between STRN exon 6 and PDGFRA exon 12.

Description	The N-term STRN - C-term PDGFRA fusion protein retains the caveolin-binding domain, the coiled-coil domain, and the calmodulin-binding domain, but not the WD-repeats of STRN, fused to a truncated WW-like domain and the kinase domain of PDGFRA; the coiled-coil domain from STRN may act as a dimerization motif that could constitutively activate PDGFRA tyrosine kinase.

Written	05-2008	Jean-Loup Huret
		Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers, France