Disease relevance of PDGFRA

• FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia [1].
• The EOL-1 cell line as an in vitro model for the study of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia [2].
• Similarly, the drug has now been shown to display equally impressive therapeutic activity in eosinophilia-associated chronic myeloproliferative disorders that are characterized by activating mutations of either the PDGFRB or the PDGFRA gene [3].
• FIP1L1-PDGFRA is a relatively infrequent but treatment-relevant mutation in primary eosinophilia that is indicative of an underlying systemic mastocytosis [1].
• KIT was amplified in 47% and VEGFR2 in 39% of the glioblastomas, respectively, and PDGFRA in 29% [4].

Psychiatry related information on PDGFRA

• Using DNA of a patient with piebaldism, mental retardation, and multiple congenital anomalies associated with a 46,XY,del(4) (q12q21.1) karyotype, we carried out quantitative Southern blot hybridization analyses of the KIT gene and the adjacent PDGFRA (platelet-derived growth factor receptor alpha subunit) genes [5].

High impact information on PDGFRA

• There is an increasing awareness that genetic polymorphisms may have an important role in the susceptibility for NTDs (ref. 6). Here we identify five different haplotypes in the human PDGFRA promoter, of which the two most abundant ones, designated H1 and H2 alpha, differ in at least six polymorphic sites [6].
• These results provide the first insight into the genetic regulation of medulloblastoma metastasis and are the first to suggest a role for PDGFRA and the RAS/MAPK signaling pathway in medulloblastoma metastasis [7].
• Notably, platelet-derived growth factor receptor alpha (PDGFRA) and members of the downstream RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway are upregulated in M+ tumors [7].
• Imatinib and sunitinib resistance generally result from secondary mutations in the KIT and/or PDGFRA kinase domains [8].
• Most gastrointestinal stromal tumors (GISTs) contain oncogenic KIT or PDGFRA receptor tyrosine kinase mutations [8].

Chemical compound and disease context of PDGFRA

• CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy [9].
• Mutation and expression of PDGFRA and KIT in malignant peripheral nerve sheath tumors, and its implications for imatinib sensitivity [10].
• A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome [11].
• Myeloproliferative hypereosinophilic syndrome (MHES) is a disorder characterised by male predominance, marked eosinophilia, splenomegaly, tissue fibrosis, elevated serum tryptase and the presence of the FIP1L1/PDGFRA fusion gene in peripheral blood mononuclear cells [12].
• In Tera-2 embryonal carcinoma cells, PDGFRA expression is strongly enhanced upon differentiation induced by retinoic acid and cAMP treatment [13].

Biological context of PDGFRA

• A bedside-to-benchtop translational research effort led to the identification of a constitutively activated fusion tyrosine kinase on chromosome 4q12, derived from an interstitial deletion, that fuses the platelet-derived growth factor receptor-alpha gene (PDGFRA) to an uncharacterized human gene FIP1-like-1 (FIP1L1) [14].
• Furthermore, approximately 40% of responding patients lack the FIP1L1-PDGFRA fusion, suggesting genetic heterogeneity [14].
• Mutational analysis of exons 9, 11, 13, and 17 of KIT, and exons 12 and 18 of PDGFRA was performed in all cases by denaturing high-pressure liquid chromatography (DHPLC) pre-screening, followed by direct sequencing [15].
• However, although the incidence of MPD involving translocations of PDGFRB has been well established, to our knowledge there are only two previous reports describing a BCR-PDGFRA fusion gene, in 3 patients diagnosed with atypical CML [16].
• Here, we report the molecular and cytogenetic characterization of a patient with BCR-PDGFRA-positive MPD who had a complete hematologic response after treatment with imatinib mesylate [16].

Anatomical context of PDGFRA

• One cell line, EOL-1, expressed the FIP1L1-PDGFRA fusion [2].
• Imatinib mesylate is a small molecule drug that in vitro inhibits the Abelson (Abl), Arg (abl-related gene), stem cell factor receptor (Kit), and platelet-derived growth factor receptor A and B (PDGFRA and PDGFRB) tyrosine kinases [3].
• The bone marrow mast cell infiltration pattern in FIP1L1-PDGFRA(+) SMCD-eos was distinctly diffuse with loose tumoral aggregates [1].
• Deletion of this locus and expression of the FIP1L1-platelet-derived growth factor receptor alpha (PDGFRA) fusion was also documented in enriched eosinophils, neutrophils, or mononuclear cells by both FISH and reverse transcriptase-polymerase chain reaction (RT-PCR) for one patient [9].
• The gene encoding the alpha-subunit of the human platelet-derived growth factor receptor (PDGFRA) maps to band q11-q12 of chromosome 4 by in situ hybridization, which was confirmed by Southern analysis of a Chinese hamster x human cell hybrid that retains only human chromosome 4 [17].

Associations of PDGFRA with chemical compounds

• Treatment with low-dose imatinib (100 mg/d) produced complete and durable responses in all 8 FIP1L1-PDGFRA(+) cases treated [1].
• Three tumours harboured PDGFRA exon 18 activating mutations; two were Asp --> Val(842) missense substitutions and one was a DIM842-844 amino acid deletion [15].
• These rare neoplasms are remarkably sensitive to the KIT and PDGFRA kinase inhibitors imatinib (also known as Gleevec) and sunitinib (Sutent), which have recently been approved as the standard therapeutic courses for patients with inoperable GIST [8].
• We detected a germline PDGFRA missense mutation, 2675G > T, resulting in a tyrosine substitution for the highly conserved aspartic acid at codon 846 [18].
• Alternately, the mutant kinase proteins can be targeted using HSP90 inhibitors, which result in degradation of activated KIT and/or PDGFRA, or using KIT transcriptional repressors, such as flavopiridol [8].
• This study is the largest reported to date on patients with advanced PDGFRA-mutant GISTs treated with imatinib [19].

Physical interactions of PDGFRA

• All three matrices have been shown to purify a 90-kDa protein that is recognized by mAbs specific for the PDGF-R alpha extracellular domain. sPDGF-R alpha is capable of binding PDGF ligand in solution and can compete with cell-associated PDGF receptors for ligand binding [20].

Regulatory relationships of PDGFRA

• This case likely represents an example of GIST with PDGFRA activating mutation and PDGFRA immunoreactivity without CD117 positivity, which has not been documented in the literature [21].
• In addition, PDGF-BB, in the presence of anti-PDGF-R beta, bound only to PDGF-R alpha and caused suppression of SMC migration induced by fibronectin [22].
• The TGF-beta 1-induced down-regulation of the PDGF-R alpha gene was rapid (maximal suppression by 2 h post-treatment) and preceded the decrease in cell-surface alpha-receptor (maximal reduction by 6 h post-treatment) [23].
• AF tumors expressed minimal to null levels of KIT and PDGFRA but expressed levels of PDGFRB that are comparable with normal fibroblasts [24].
• Intestinal Neurofibromatosis Is a Subtype of Familial GIST and Results From a Dominant Activating Mutation in PDGFRA [25].

Other interactions of PDGFRA

• This review examines the current state of knowledge of HES and CEL and the implications of the FIP1L1-PDGFRA discovery on their diagnosis, classification, and management [14].
• No mutations were detected with denaturing high-performance liquid chromatography in KIT exons 9, 11, 13 or 17, PDGFRA exons 12 and 18, or EGFR exons 18, 19 or 21 [4].
• In summary, PDGFRA, PDGF and KIT dysregulation as well as growth inhibition of cell culture S462 by imatinib may suggest that MPNST patients benefit from treatment with imatinib [10].
• Point mutations of c-kit gene or PDGFRA gene were identified only in three (8%) and two (6%) tumors, respectively [26].
• This article describes the results of comprehensive molecular/biochemical analyses of the three receptors targeted by the drug (PDGFRB, PDGFRA, and KIT) in a series of 31 chordoma patients [27].

Analytical, diagnostic and therapeutic context of PDGFRA

• A fluorescence in situ hybridization (FISH)-based strategy was used to detect FIP1L1-PDGFRA in bone marrow cells [1].
• PDGFRA was amplified in seven tumours from six patients and MPNST cell culture S462 [10].
• Endoscopic ultrasonography (EUS)-guided fine-needle aspiration biopsy (EUS-FNAB) is a useful method for the diagnosis of GIST and for the detection of KIT or PDGFRA mutations [28].
• Since other translocations in MPDs frequently involve tyrosine kinases, we designed a multiplex PCR to search for mRNA fusions between BCR and three potential partner genes at 4q12: KIT, KDR and PDGFRA [29].
• Three relevant principal component representing mutation of KIT, PDGFRA and chromosome 14q deletion were identified from the interpretation of the oligonucleotide microarray data with PCA [30].

References