t(4;5)(q21;q33) PRKG2/PDGFRB

2009-11-01   Jean-Loup Huret  

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

Clinics and Pathology

Disease

Atypical myeloproliferative disease (a-MPD) and systemic mast cell disease (SMCD)

Epidemiology

3 cases to date, a 45-year-old female patient with a-MPD with basophilia and eosinophilia (Walz et al., 2007), a 61-year-old male patient with systemic mast cell disease (SMCD) and an associated chronic basophilic leukemia (Lahortiga et al., 2008), and a 45-year-old male patient with a SMCD with eosinophilia (Gallagher et al., 2008).

Prognosis

This translocation seems to respond well to imatinib therapy: the chromosomal anomaly disappered with imatinib in the first patient; in the second case, the patient remained in clinical and cytogenetic remission 3 years after imatinib was initiated; the third patient was alive and well after about 4 years of therapy with imatinib.

Genes Involved and Proteins

Note
The patient with SMCD and an associated chronic basophilic leukemia was negative for KIT mutations (Lahortiga et al., 2008).
Gene name
PRKG2 (protein kinase, cGMP-dependent, type II)
Location
4q21.21
Protein description
762 amino acids; comprises a coiled-coil domain (leucine zipper, amino acids 23-85), cGMP binding sites (168-285 and 286-417) and a serine-threonine kinase domain (453-711); involved in signaling pathway. Belongs to the family of cyclic GMP-dependent protein kinase. PRKG2 phosphorylates CFTR. PRKG2 is an ion transport regulator (Vaandrager et al., 2005). PRKG2 regulates SOX9-mediated transcription of collagen 2 through phosphorylation (Chikuda et al., 2004). It was found that PRKG2 has an anti-proliferative effect via suppression of SOX9 expression, inhibition of Akt phosphorylation, and G1 arrest in glioma cell lines (Swartling et al., 2009).
Gene name
PDGFRB (platelet-derived growth factor receptor, beta polypeptide)
Location
5q32
Protein description
Comprises an extracellular part with 5 Ig-like C2 type domains, a transmembrane domain, and an intracellular part with a tyrosine kinase domain (made of two tyrosine kinase subdomains) for transduction of the signal. Receptor tyrosine kinase; receptor for PDGFB and PDGFD (Bergsten et al., 2001); forms homodimers, or heterodimer with PDGFRA; upon dimerization, subsequent activation by autophosphorylation of the tyrosine kinase intracellular domains occurs.

Result of the Chromosomal Anomaly

Description

5 PRKG2 - 3 PDGFRB. In-frame fusion between exon 2 of PRKG2, a 5 bp insert derived from intron 2 of PRKG2, and a truncated version (last 33 bp) of exon 12 of PDGFRB in one case (Lahortiga et al., 2008), and In-frame fusion between exon 5 of PRKG2, a 17 bp insert derived from PRKG2 intron 5, and a 41 bp truncated version exon 12 of PDGFRB in another case (Walz et al., 2007).

Oncogenesis

The coiled-coil domain from PRKG2 would favour dimerization, with subsequent constitutive activation of the PDGFRB tyrosine kinase domain.

Highly cited references

Pubmed IDYearTitleCitations
181667852008Activity of imatinib in systemic mastocytosis with chronic basophilic leukemia and a PRKG2-PDGFRB fusion.15
284122132017Acute mast cell leukemia associated with t(4;5)(q21;q33).3
276483152016A 26-Year-Old Female with Systemic Mastocytosis with Associated Myeloid Neoplasm with Eosinophilia and Abnormalities of PDGFRB, t(4;5)(q21;q33).2
336630812021Myeloid tumors accompanying systemic mastocytosis, basophilia, and abnormal platelet-derived growth factor receptor β: A case report.0

Article Bibliography

Pubmed IDLast YearTitleAuthors
113318812001PDGF-D is a specific, protease-activated ligand for the PDGF beta-receptor.Bergsten E et al
154664902004Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes.Chikuda H et al
182620532008Fusion of PRKG2 and SPTBN1 to the platelet-derived growth factor receptor beta gene (PDGFRB) in imatinib-responsive atypical myeloproliferative disorders.Gallagher G et al
181667852008Activity of imatinib in systemic mastocytosis with chronic basophilic leukemia and a PRKG2-PDGFRB fusion.Lahortiga I et al
195433192009Cyclic GMP-dependent protein kinase II inhibits cell proliferation, Sox9 expression and Akt phosphorylation in human glioma cell lines.Swartling FJ et al
159704842005Molecular properties and biological functions of cGMP-dependent protein kinase II.Vaandrager AB et al
172965642007Characterization of three new imatinib-responsive fusion genes in chronic myeloproliferative disorders generated by disruption of the platelet-derived growth factor receptor beta gene.Walz C et al

Summary

Fusion gene

PRKG2/PDGFRB PRKG2 (4q21.21) PDGFRB (5q32) M|PRKG2/PDGFRB PRKG2 (4q21.21) PDGFRB (5q32) M t(4;5)(q21;q32)|PRKG2/PDGFRB PRKG2 (4q21.21) PDGFRB (5q32) TIC

Citation

Jean-Loup Huret

t(4;5)(q21;q33) PRKG2/PDGFRB

Atlas Genet Cytogenet Oncol Haematol. 2009-11-01

Online version: http://atlasgeneticsoncology.org/haematological/1510/t(4;5)(q21;q33)