The myxoid liposarcoma FUS-DDIT3 fusion oncoprotein deregulates NF-κB target genes by interaction with NFKBIZ

Göransson, Melker; Andersson, Mattias K.; Forni, Claudia; Ståhlberg, Anders; Andersson, Christian X.; Olofsson, Anita; Mantovani, Roberto; Åman, Pierre

doi:10.1038/onc.2008.378

Cited by 71 publications

(73 citation statements)

References 48 publications

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“…The C-terminus of FUS co-activates p65 and plays a pivotal role in NF-kappaB mediated transcription though this C-terminus is lost in the FUS/DDIT3 fusion protein. Recent studies showed that the FUS/DDIT3 fusion protein facilitates NF-kappaB binding to its target genes, probably in an indirect manner[19,39-41]. The FUS-DDIT3 fusion protein deregulates NF-kappaB controlled genes by interaction with nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor zeta (NFKBIZ)[19].…”

Section: Discussionmentioning

confidence: 99%

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Kinome profiling of myxoid liposarcoma reveals NF-kappaB-pathway kinase activity and Casein Kinase II inhibition as a potential treatment option

et al. 2010

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BackgroundMyxoid liposarcoma is a relatively common malignant soft tissue tumor, characterized by a (12;16) translocation resulting in a FUS-DDIT3 fusion gene playing a pivotal role in its tumorigenesis. Treatment options in patients with inoperable or metastatic myxoid liposarcoma are relatively poor though being developed and new hope is growing.ResultsUsing kinome profiling and subsequent pathway analysis in two cell lines and four primary cultures of myxoid liposarcomas, all of which demonstrated a FUS-DDIT3 fusion gene including one new fusion type, we aimed at identifying new molecular targets for systemic treatment. Protein phosphorylation by activated kinases was verified by Western Blot and cell viability was measured before and after treatment of the myxoid liposarcoma cells with kinase inhibitors. We found kinases associated with the atypical nuclear factor-kappaB and Src pathways to be the most active in myxoid liposarcoma. Inhibition of Src by the small molecule tyrosine kinase inhibitor dasatinib showed only a mild effect on cell viability of myxoid liposarcoma cells. In contrast, inhibition of the nuclear factor-kappaB pathway, which is regulated by the FUS-DDIT3 fusion product, in myxoid liposarcoma cells using casein kinase 2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) showed a significant decrease in cell viability, decreased phosphorylation of nuclear factor-kappaB pathway proteins, and caspase 3 mediated apoptosis. Combination of dasatinib and TBB showed an enhanced effect.ConclusionKinases associated with activation of the atypical nuclear factor-kappaB and the Src pathways are the most active in myxoid liposarcoma in vitro and inhibition of nuclear factor-kappaB pathway activation by inhibiting casein kinase 2 using TBB, of which the effect is enhanced by Src inhibition using dasatinib, offers new potential therapeutic strategies for myxoid liposarcoma patients with advanced disease.

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Section: Discussionmentioning

confidence: 99%

“…Data on activated pathways in myxoid liposarcoma are sparse[18,19]. By using a kinase substrate specific protein array chip combining 1024 different kinase substrates, we identified kinases associated with Src and NF-kappaB pathways to be active in myxoid liposarcoma.…”

Section: Introductionmentioning

confidence: 99%

Kinome profiling of myxoid liposarcoma reveals NF-kappaB-pathway kinase activity and Casein Kinase II inhibition as a potential treatment option

et al. 2010

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“…At the genetic level, the most characteristic change is a t(12;16) (q13;p11) chromosomal translocation that results in the fusion of the FUS and DDIT3 genes (16,17). The cellular origin of these tumors is unknown, but preadipocytic progenitor cells and mesenchymal stem cells have been implicated (18); after embryogenesis, the mitotic activity of these cells is thought to be low.…”

Section: Resultsmentioning

confidence: 99%

TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal

Killela

Reitman

Jiao

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

1,244

1,230

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Malignant cells, like all actively growing cells, must maintain their telomeres, but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/ mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telomerase expression and have been shown to occur in melanomas and a small number of other tumors. To further define the tumor types in which this latter mechanism plays a role, we surveyed 1,230 tumors of 60 different types. We found that tumors could be divided into types with low (<15%) and high (≥15%) frequencies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas (including 83% of primary glioblastoma, the most common brain tumor type). TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages. In addition to their implications for understanding the relationship between telomeres and tumorigenesis, TERT mutations provide a biomarker that may be useful for the early detection of urinary tract and liver tumors and aid in the classification and prognostication of brain tumors.

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“…Recurrent translocations have typically been interpreted as important for tumorigenesis, and, for example, the FUS-DDIT3 gene fusion has been described as oncogenic in liposarcoma. 189 However, there is growing evidence that recurrent translocations can also be passenger events in cancer. 190 In conclusion, there is increasing evidence of the extent and importance of aberrant splicing in cancer.…”

Section: Dysregulation Of Splicing In Cancermentioning

confidence: 99%

Aberrant RNA splicing in cancer; expression changes and driver mutations of splicing factor genes

Sveen

Kilpinen²,

Ruusulehto³

et al. 2015

Oncogene

418

412

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Alternative splicing is a widespread process contributing to structural transcript variation and proteome diversity. In cancer, the splicing process is commonly disrupted, resulting in both functional and non-functional end-products. Cancer-specific splicing events are known to contribute to disease progression; however, the dysregulated splicing patterns found on a genome-wide scale have until recently been less well-studied. In this review, we provide an overview of aberrant RNA splicing and its regulation in cancer. We then focus on the executors of the splicing process. Based on a comprehensive catalog of splicing factor encoding genes and analyses of available gene expression and somatic mutation data, we identify cancer-associated patterns of dysregulation. Splicing factor genes are shown to be significantly differentially expressed between cancer and corresponding normal samples, and to have reduced inter-individual expression variation in cancer. Furthermore, we identify enrichment of predicted cancer-critical genes among the splicing factors. In addition to previously described oncogenic splicing factor genes, we propose 24 novel cancer-critical splicing factors predicted from somatic mutations.

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The myxoid liposarcoma FUS-DDIT3 fusion oncoprotein deregulates NF-κB target genes by interaction with NFKBIZ

Cited by 71 publications

References 48 publications

Kinome profiling of myxoid liposarcoma reveals NF-kappaB-pathway kinase activity and Casein Kinase II inhibition as a potential treatment option

Kinome profiling of myxoid liposarcoma reveals NF-kappaB-pathway kinase activity and Casein Kinase II inhibition as a potential treatment option

TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal

Aberrant RNA splicing in cancer; expression changes and driver mutations of splicing factor genes

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