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Bennani-Baiti I.M.,Childrens Cancer Research Institute
Epigenomics | Year: 2011

Sarcomas comprise a large number of rare, histogenetically heterogeneous, mesenchymal tumors. Cancers such as Ewing's sarcoma, liposarcoma, rhabdomyosarcoma and synovial sarcoma can be generated by the transduction of mesenchymal stem cell progenitors with sarcoma-pathognomonic oncogenic fusions, a neoplastic transformation process accompanied by profound locus-specific and pangenomic epigenetic alterations. The epigenetic activities of histone-modifying and chromatin-remodeling enzymes such as SUV39H1/KMT1A, EZH2/KMT6A and BMI1 are central to epigenetic-regulated transformation, a property we coin oncoepigenic. Sarcoma-specific oncoepigenic aberrations modulate critical signaling pathways that control cell growth and differentiation including several miRNAs, Wnt, PI3K/AKT, Sav-RASSF1-Hpo and regulators of the G1 and G2/M checkpoints of the cell cycle. Herein an overview of the current knowledge of this rapidly evolving field that will undoubtedly uncover additional oncoepigenic mechanisms and yield druggable targets in the near future is discussed. © 2011 Future Medicine Ltd. Source

Lawitschka A.,Childrens Cancer Research Institute | Ball L.,Leiden University | Peters C.,Stem Cell Transplantation Unit
Biology of Blood and Marrow Transplantation | Year: 2012

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many children with life-threatening diseases. One of the most significant long-term complications of transplantation is chronic graft-versus-host disease (cGVHD). Although the rates of cGVHD after HSCT are lower in the pediatric population than in adults, cGVHD remains a significant cause of morbidity and mortality. Medicines used to prevent and treat cGVHD remain unsatisfactory, with protracted use of immune suppression necessary and high rates of first-line treatment failure. Efforts to improve salvage treatment are urgently required. Nonpharmacologic strategies attempt to modulate the cellular inflammation response and possibly allow reduction or cessation of immunosuppressive drugs. Mesenchymal stromal cells (MSC) have been shown invitro to mediate a wide variety of immune responses. MSC have been used in the prophylaxis of acute GVHD (aGVHD) and for the treatment of established steroid refractory aGVHD and, more recently, in the management of cGVHD. Extracorporeal photochemotherapy (ECP) has shown promising efficacy in graft-versus-host disease, and may allow a significant reduction in the use of systemic steroids and other immunosuppressants, reducing long-term morbidity and mortality. The accumulated experience shows ECP to be well tolerated, with no clinically significant side effects. © 2012 American Society for Blood and Marrow Transplantation. Source

Bennani-Baiti B.,University of Vienna | Bennani-Baiti I.M.,Childrens Cancer Research Institute
Gene | Year: 2012

Several gene databases, including heavily used ones such as the National Center for Biotechnology Information (NCBI) database, erroneously assign, on occasion, literature references to genes or proteins. These mistakes are mostly due to an overlap in gene aliases, whereby two distinct genes share a pseudonym. This is particularly confusing when the gene products have also biological properties in common, are part of signaling pathways that cross-talk to one another, or are regulated by the same effectors. We present examples spanning several research fields including apoptosis, ubiquitin-dependent degradation, signaling by Notch, Wnt, and small G proteins, transporters of glutathione conjugates of electrophiles, and mitochondrial and ribosomal RNA genes. To solve the problem, we argue in favor of including Entrez gene numbers in papers submitted for publication as unique gene identifiers to allow precise identification of genes and species studied. © 2011 Elsevier B.V. Source

Kovar H.,Childrens Cancer Research Institute
Sarcoma | Year: 2011

FUS, EWS, and TAF15 form the FET family of RNA-binding proteins whose genes are found rearranged with various transcription factor genes predominantly in sarcomas and in rare hematopoietic and epithelial cancers. The resulting fusion gene products have attracted considerable interest as diagnostic and promising therapeutic targets. So far, oncogenic FET fusion proteins have been regarded as strong transcription factors that aberrantly activate or repress target genes of their DNA-binding fusion partners. However, the role of the transactivating domain in the context of the normal FET proteins is poorly defined, and, therefore, our knowledge on how FET aberrations impact on tumor biology is incomplete. Since we believe that a full understanding of aberrant FET protein function can only arise from looking at both sides of the coin, the good and the evil, this paper summarizes evidence for the central function of FET proteins in bridging RNA transcription, processing, transport, and DNA repair. Copyright © 2011 Heinrich Kovar. Source

Kovar H.,Childrens Cancer Research Institute
Genome Medicine | Year: 2010

Ewing's sarcoma family tumors are a good example of how genome research has advanced our understanding of the molecular pathogenesis of an otherwise enigmatic disease. This group of embryonal bone tumors is characterized by the expression of a chimeric ETS-family oncogene, predominantly EWS/FLI1. There is now convincing evidence for a mesenchymal descent from an early pluripotent progenitor. EWS/FLI1 has been shown to drive proliferation of Ewing's sarcoma cells and block most of the differentiation potential except for a partial neural gene expression program. The EWS/FLI1 fusion protein acts mainly as a gene activator, directly interacting with chromatin at two kinds of binding site: distant enhancers enriched in GGAA microsatellites, and proximal promoters containing classical ETS-binding motifs and recognition motifs for other transcription factors. EWS/FLI1 also represses a large number of genes, mainly indirectly, presumably by altering microRNA expression and epigenetic mechanisms, and potentially affecting post-transcriptional gene regulation. Modulation of EWS/FLI1 expression is not only a desirable therapeutic goal, but may also occur under physiological conditions and influence the course of the disease. © 2010 BioMed Central Ltd. Source

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