The molecular pathogenesis of Ewing sarcoma

Mackintosh, Carlos; Madoz‐Gúrpide, Juan; Ordóñez, José Luis; Osuna, Daniel; Herrero-Martín, David

doi:10.4161/cbt.9.9.11511

Cited by 66 publications

(61 citation statements)

References 197 publications

(223 reference statements)

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“…Ewing sarcoma (ES) a bone and soft tissue malignancy is characterized by early metastasis to lung and bone [1]. Here we observed genes such as HOXD10, HOXD11 and HOXD13 normally involved in bone formation and ossification pattern of bones [22], to be HOXD locus including HOXD9 and HOXD12 where not uniquely up-regulated in primary ES compared to other tumors.…”

Section: Discussionmentioning

confidence: 68%

“…In search for factors presumably involved in their increased expression in ES we investigated putative ES originating cells such as neural crest or mesenchymal stem cells [1][2][3]. Though, genes of the HOXD locus were already expressed in mesenchymal or neural crest derived cells ( Figure 1B), they were not increased early after up-regulation of EWS-FLI1 in such stem cells nor did EWS-FLI1 knock down in ES lines influence HOXD10, HOXD11 or HOXD13 expression in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…These highly malignant sarcomas frequently arise in diaphysal bones possibly descending from a neuroectodermal or mesenchymal stem cell in transition from an undifferentiated state to a more differentiated phenotype of the chondro-osseous lineage [1][2][3][4][5][6]. Genetically, ES are defined by EWS/ETS translocations [1,7,8].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The posterior HOXD locus: Its contribution to phenotype and malignancy of Ewing sarcoma

Heyking¹,

Roth²,

Ertl³

et al. 2016

European Journal of Cancer

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The posterior HOXD locus: Its contribution to phenotype and malignancy of Ewing sarcoma

Heyking¹,

Roth²,

Ertl³

et al. 2016

European Journal of Cancer

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“…[25][26][27][28] However, the addition of adjunctive, immune-activating therapies during first remission demonstrated the potential to reduce recurrence rates and exploit immunotherapy approaches for ES patients. 29 Balanced chromosomal EWS/ETS translocations that give rise to oncogenic chimeric proteins (EWS-ETS), the most common being EWS-FLI1 as a consequence of the t(11;22)(q24; q12) translocation, 30,31 are the characteristic driver event of ES tumorgenesis. 32 However, despite an MHC-class-II-restricted peptide derived from the fusion region of EWS-FLI1 that is able to initiate a CD4 C T-cell response, 33 no immunogenic ESspecific MHC-class-I-binding peptides derived from this fusion region have been identified, 34 prompting the search for further immunogenic epitopes of this disease.…”

Section: Discussionmentioning

confidence: 99%

Transgenic antigen-specific, HLA-A*02:01-allo-restricted cytotoxic T cells recognize tumor-associated target antigen STEAP1 with high specificity

Schirmer¹,

Grünewald²,

Klar³

et al. 2016

OncoImmunology

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“…1A). In Ewing's sarcoma, fusion oncogenes, generated by chromosome translocation, encode the N terminus of the EWS protein and the DNA-binding domains of ERG, FLI1, FEV, ETV1, or ETV4 (Mackintosh et al 2010). The difference between the prostate-and Ewing's sarcoma-related subsets of ETS proteins is likely due to the inclusion of the N terminus of EWS, which imparts novel transcriptional functions and is required for transformation (May et al 1993).…”

Section: Role Of Ets Genes In Other Cancersmentioning

confidence: 99%

Oncogenic ETS proteins mimic activated RAS/MAPK signaling in prostate cells

Hollenhorst¹,

Ferris²,

Hull³

et al. 2011

Genes Dev.

140

207

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The aberrant expression of an oncogenic ETS transcription factor is implicated in the progression of the majority of prostate cancers, 40% of melanomas, and most cases of gastrointestinal stromal tumor and Ewing's sarcoma. Chromosomal rearrangements in prostate cancer result in overexpression of any one of four ETS transcription factors. How these four oncogenic ETS genes differ from the numerous other ETS genes expressed in normal prostate and contribute to tumor progression is not understood. We report that these oncogenic ETS proteins, but not other ETS factors, enhance prostate cell migration. Genome-wide binding analysis matched this specific biological function to occupancy of a unique set of genomic sites highlighted by the presence of ETS-and AP-1-binding sequences. ETS/AP-1-binding sequences are prototypical RAS-responsive elements, but oncogenic ETS proteins activated a RAS/MAPK transcriptional program in the absence of MAPK activation. Thus, overexpression of oncogenic ETS proteins can replace RAS/MAPK pathway activation in prostate cells. The genomic description of this ETS/AP-1-regulated, RAS-responsive, gene expression program provides a resource for understanding the role of these ETS factors in both an oncogenic setting and the developmental processes where these genes normally function.[Keywords: prostate cancer; ETS; ChIP-seq; RAS/MAPK; cell migration] Supplemental material is available for this article. In cancer cells, aberrant gene expression programs result from alterations in the signaling pathways that regulate transcription factor function, or from the mutation or altered expression of transcription factors themselves. Deciphering the role of a transcription factor requires understanding how these proteins are targeted to specific genomic binding sites, how they influence transcription once bound, and how these functions are modified by signaling pathways. However, overlapping functions among the thousands of transcription factors encoded by the human genome has made it difficult to assign specific oncogenic mechanisms.The ETS family of transcription factors exemplifies this specificity problem (Hollenhorst et al. 2011a). The 28 human ETS proteins bind DNA via a conserved ETS DNAbinding domain and recognize similar DNA sequences. All ETS proteins bind sites with the core sequence GGA and most bind with highest affinity to the extended consensus CCGGAAGT (Wei et al. 2010). This lack of intrinsic DNA sequence specificity is contrasted by unique biological functions for each ETS family member (Hollenhorst et al. 2011a). We showed previously that genomic targets of ETS transcription factors can include two distinct classes (Hollenhorst et al. 2007(Hollenhorst et al. , 2009. First are the ''redundant'' binding sites found in the proximal promoters of housekeeping genes. Binding sites in this class are characterized by the consensus ETS sequence (CCGGAAGT) and thus have the potential to bind any ETS protein with relatively high affinity. Second are the ''specific'' binding sites that are found...

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The molecular pathogenesis of Ewing sarcoma

Cited by 66 publications

References 197 publications

The posterior HOXD locus: Its contribution to phenotype and malignancy of Ewing sarcoma

The posterior HOXD locus: Its contribution to phenotype and malignancy of Ewing sarcoma

Transgenic antigen-specific, HLA-A*02:01-allo-restricted cytotoxic T cells recognize tumor-associated target antigen STEAP1 with high specificity

Oncogenic ETS proteins mimic activated RAS/MAPK signaling in prostate cells

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