Browsing by Author "Fioretos, Thoas"

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    Fusions involving protein kinase C and membrane-associated proteinsin benign fibrous histiocytoma
    (he International Journal of Biochemistry & Cell Biology,, 2014) Płaszczyca, Anna; Nilsson, Jenny; Magnusson, Linda; Brosjö, Otte; Larsson, Olle; Vult von Steyernd, Fredrik; Domanski, Henryk A.; Lilljebjörn, Henrik; Fioretos, Thoas; Tayebwa, Johnbosco; Mandahl, Nils; Nord, Karolin H.; Mertens, Fredrik
    Benign fibrous histiocytoma (BFH) is a mesenchymal tumor that most often occurs in the skin (so-called dermatofibroma), but may also appear in soft tissues (so-called deep BFH) and in the skeleton(so-called non-ossifying fibroma). The origin of BFH is unknown, and it has been questioned whether itis a true neoplasm. Chromosome banding, fluorescence in situ hybridization, single nucleotide polymor-phism arrays, RNA sequencing, RT-PCR and quantitative real-time PCR were used to search for re current somatic mutations in a series of BFH. BFHs were found to harbor recurrent fusions of genes encoding membrane-associated proteins (podoplanin, CD63 and LAMTOR1) with genes encoding protein kinaseC (PKC) isoforms PRKCB and PRKCD. PKCs are serine–threonine kinases that through their many phos-phorylation targets are implicated in a variety of cellular processes, as well as tumor development. When inactive, the amino-terminal, regulatory domain of PKCs suppresses the activity of their catalytic domain. Upon activation, which requires several steps, they typically translocate to cell membranes, where they interact with different signaling pathways. The detected PDPN-PRKCB, CD63-PRKCD and LAMTOR1-PRKCDgene fusions are all predicted to result in chimeric proteins consisting of the membrane-binding part of PDPN, CD63 or LAMTOR1 and the entire catalytic domain of the PKC. This novel pathogenetic mechanism should result in constitutive kinase activity at an ectopic location. The results show that BFH indeed is atrue neoplasm, and that distorted PKC activity is essential for tumorigenesis. The findings also provide means to differentiate BFH from other skin and soft tissue tumors.
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    A novel SERPINE1–FOSB fusion gene results in transcriptional up-regulation of FOSB in pseudomyogenic haemangioendothelioma
    (The Journal of Pathology, 2014) Walther, Charles; Tayebwa, Johnbosco; Lilljebjorn, Henrik; Magnusson, Linda; Nilsson, Jenny; Vult von Steyern, Fredrik; Øra, Ingrid; Domanski, Henryk A.; Fioretos, Thoas; Nord, Karolin H.; Fletcher, Christopher D. M.
    Pseudomyogenic haemangioendothelioma (PHE) is an intermediate malignant vascular soft tissue tumour primarily affecting children and young adults. The molecular basis of this neoplasm is unknown. We here used chromosome banding analysis, fluorescence in situ hybridization (FISH), mRNA sequencing, RT–PCR and quantitative realtime PCR on a series of morphologically well-characterized PHEs to show that a balanced translocation, t(7;19)(q22;q13), detected as the sole cytogenetic aberration in two cases, results in fusion of the SERPINE1 and FOSB genes. This translocation has not been observed in any other bone or soft tissue tumour. Interphase FISH on sections from eight additional PHEs identified the same SERPINE1–FOSB fusion in all cases. The role of SERPINE1, which is highly expressed in vascular cells, in this gene fusion is probably to provide a strong promoter for FOSB, which was found to be expressed at higher levels in PHEs than in other soft tissue tumours. FOSB encodes a transcription factor belonging to the FOS family of proteins, which, together with members of the JUN family of transcription factors, are major components of the activating protein 1 (AP-1) complex. Further studies are needed to understand the cellular impact of the aberrant expression of the FOSB gene, but as the t(7;19) resulting in the SERPINE1–FOSB fusion seems to be pathognomonic for PHE, FISH or RT–PCR could be useful for differential diagnostic purposes.