t(2;4)(p22;q12) STRN/PDGFRA

2008-05-01   Jean-Loup Huret 

1.Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers, France

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 (striatin, calmodulin binding protein)
Location
2p22.2
Protein description
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 (platelet-derived growth factor receptor, alpha polypeptide)
Location
4q12
Protein description
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

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.

Highly cited references

Pubmed IDYearTitleCitations
175554502007Two novel imatinib-responsive PDGFRA fusion genes in chronic eosinophilic leukaemia.12
333866732021Phosflow assessment of PDGFRA phosphorylation state: A guide for tyrosine kinase inhibitor targeted therapy in hypereosinophilia patients.1

Bibliography

Pubmed IDLast YearTitleAuthors
120239812002The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA.Baxter EJ et al
164609202006The striatin family: a new signaling platform in dendritic spines.Benoist M et al
126603842003A 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
90456781997Identification of peptide and protein ligands for the caveolin-scaffolding domain. Implications for the interaction of caveolin with caveolae-associated proteins.Couet J et al
175554502007Two novel imatinib-responsive PDGFRA fusion genes in chronic eosinophilic leukaemia.Curtis CE et al
150100692004Use 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
117072662001Striatin, a calmodulin-dependent scaffolding protein, directly binds caveolin-1.Gaillard S et al
125222572003PDGFRA activating mutations in gastrointestinal stromal tumors.Heinrich MC et al
121813112002Definition of an inhibitory juxtamembrane WW-like domain in the platelet-derived growth factor beta receptor.Irusta PM et al
85864211995Structure, organization, and transcription units of the human alpha-platelet-derived growth factor receptor gene, PDGFRA.Kawagishi J et al
152841182004FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia.Pardanani A et al
164983882006Identification of a novel imatinib responsive KIF5B-PDGFRA fusion gene following screening for PDGFRA overexpression in patients with hypereosinophilia.Score J et al
168456592006Transient 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

Summary

Fusion gene

STRN/PDGFRA STRN (2p22.2) PDGFRA (4q12) M t(2;4)(p22;q12)|STRN/PDGFRA STRN (2p22.2) PDGFRA (4q12) TIC

Citation

Jean-Loup Huret

t(2;4)(p22;q12) STRN/PDGFRA

Atlas Genet Cytogenet Oncol Haematol. 2008-05-01

Online version: http://atlasgeneticsoncology.org/haematological/2136/t(2;4)(p22;q12)

External Links