Promiscuous partnerships in Ewing's sarcoma

doi:10.1016/j.cancergen.2011.07.008

Cancer Genetics

Volume 204, Issue 7, July 2011, Pages 351-365

https://doi.org/10.1016/j.cancergen.2011.07.008 Get rights and content

Ewing’s sarcoma is a highly aggressive bone and soft tissue tumor of children and young adults. At the molecular genetic level Ewing’s sarcoma is characterized by a balanced reciprocal translocation, t(11;22)(q24;q12), which encodes an oncogenic fusion protein and transcription factor EWS/FLI. This tumor-specific chimeric fusion retains the amino terminus of EWS, a member of the TET (TLS/EWS/TAF15) family of RNA-binding proteins, and the carboxy terminus of FLI, a member of the ETS family of transcription factors. In addition to EWS/FLI, variant translocation fusions belonging to the TET/ETS family have been identified in Ewing’s sarcoma. These studies solidified the importance of TET/ETS fusions in the pathogenesis of Ewing’s sarcoma and have since been used as diagnostic markers for the disease. EWS fusions with non-ETS transcription factor family members have been described in sarcomas that are clearly distinct from Ewing’s sarcoma. However, in recent years there have been reports of rare fusions in “Ewing’s-like tumors” that harbor the amino-terminus of EWS fused to the carboxy-terminal DNA or chromatin-interacting domains contributed by non-ETS proteins. This review aims to summarize the growing list of fusion oncogenes that characterize Ewing’s sarcoma and Ewing’s-like tumors and highlights important questions that need to be answered to further support the existing concept that Ewing’s sarcoma is strictly a “TET/ETS” fusion-driven malignancy. Understanding the molecular mechanisms of action of the various different fusion oncogenes will provide better insights into the biology underlying this rare but important solid tumor.

Section snippets

The EWS/FLI fusion in Ewing’s sarcoma

Karyotypically, Ewing’s sarcoma is a relatively simple neoplasm, harboring the main cytogenetic hallmark t(11;22)(q24;q12) translocation 9, 18. Approximately 85% of Ewing’s sarcoma tumors harbor this characteristic translocation. The t(11;22) rearrangement creates a fusion between the Ewing’s sarcoma breakpoint region 1 gene (EWSR1) on chromosome 22 and the Friend leukemia virus integration site 1 gene (FLI1) on chromosome 11 (19) (Figure 1A).

The EWSR1 gene encodes the EWS protein, which is a

EWS/FLI fusion subtypes

“EWS/FLI” is not a single molecular entity, but rather includes a set of highly related isoforms or subtypes. This diversity is a result of differences in genomic breakpoints in the EWSR1 and FLI1 genes. Breakpoints have been observed in a variety of introns in these genes 66, 67, 68. In each case, the resultant fusion is really in the introns of the genes, and through typical splicing processes of the transcribed RNA, fusion mRNAs are generated containing 5′ exons derived from EWSR1 fused to

Other EWS/ETS fusions in Ewing’s sarcoma

The ETS family of proteins is comprised of transcription factors that are characterized by the presence of a highly conserved 85 amino acid ETS domain that mediates sequence-specific DNA binding (27). In many cases, ETS proteins function as signal-dependent transcriptional regulators controlling cellular differentiation and proliferation 74, 75. Many different members of the ETS family have been shown to be involved in oncogenesis, predominantly, by chromosomal translocations that fuse ETS

TET/ETS fusions in Ewing’s sarcoma

To further add to the complexity of Ewing’s sarcoma, non-EWS fusions have been identified in rare cases of the disease. As discussed above, EWS is a member of the TET (TLS/EWS/TAF15) family of proteins. Gene fusions have been identified between the TET family member TLS (also called FUS) and two different ETS family members, ERG and FEV (Figure 2). TLS/ERG and TLS/FEV fusion proteins are found in <1% of Ewing’s sarcoma cases. Conceptually, again, these “TLS/ETS” fusions are likely to

EWS/NFATc2

In 2009 there was a report on the identification of a new translocation partner of the EWSR1 gene, NFATc2 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 also known as NFAT1 or NFATp), in “Ewing’s-like tumors” (94). In all cases identified, an in-frame chimeric fusion between exon 8 of EWSR1 and exon 3 of the NFATc2 gene was identified (Figure 3). The EWS/NFATc2 fusion harboring solid tumors were diagnosed in four male patients who were 16, 21, 25 and 39 years of age.

Cell-of-origin and cellular context in Ewing’s sarcoma

One important aspect that is crucial to understanding the biology of Ewing’s sarcoma is the identification and characterization of the cell-of-origin for the disease. Currently there is no resolution to this issue. On the one hand, there is a growing body of work suggestive of a mesenchymal stem or progenitor cell as the precursor cell type for Ewing’s sarcoma 118, 119, 120, 121, 122. On the other hand, several observations are consistent with a neural crest cell-of-origin 123, 124, 125.

Potential mechanisms of chromosomal translocations in Ewing’s sarcoma

There is relatively little known about the mechanism of generation of TET/ETS (and non-TET/ETS) chromosomal translocations in Ewing’s and Ewing’s-like tumors, but a few hypotheses have been advanced since the discovery of EWS/FLI nearly 20 years ago. Homologous recombination at site-specific sequences has been suggested as the potential mechanism of chromosomal translocations in human hematological malignancies such as lymphoid neoplasms (139). In contrast, analysis of 113 interchromosomal

Is it time to revisit the concept that TET/ETS fusions are pathognomonic for Ewing’s sarcoma?

The initial discovery of EWS/FLI and the demonstration that this fusion functions as an aberrant transcription factor to mediate oncogenesis in Ewing’s sarcoma provided a simple model for Ewing’s sarcoma tumorigenesis: EWS/FLI sits at the top of a transcriptional hierarchy to dysregulate a set of target genes that together mediate tumor formation. The discovery of the EWS/ERG fusion, with its highly conserved domain structure to EWS/FLI, provided additional support for this hypothesis. Indeed,

Should we care if non-TET/ETS-containing tumors are Ewing’s sarcoma?

Ewing’s sarcoma itself is a rare tumor, with approximately 250 new cases occurring in the United States each year (145). If each of the rare TET/ETS and non-TET/ETS fusion variants occurs in 1% of cases or less, these will contribute to a very small portion, and a very small total number of tumors. Are these an important set of tumors to understand?

We would suggest that these are indeed important tumors to understand. In the first place, patients will develop tumors harboring these rare fusion

Summary and conclusions

Ewing’s sarcoma is an enigmatic cancer driven by chromosomal translocation derived fusion oncogenes. TET/ETS proteins are undoubtedly the central mediators in the pathogenesis of Ewing’s sarcoma. In particular EWS/FLI, the most common gene rearrangement in Ewing’s sarcoma, is widely used as a molecular diagnostic marker for the disease. However, recent identification of an increasing number of similar TET/ETS as well as non-TET/ETS rearrangements has further complicated molecular diagnostics

Acknowledgments

S.S. is a University of Utah Howard Hughes Medical Institute Med into Grad Program Scholar. S.L.L. is supported by the NIH (R21 CA138295, R01 CA140394), the Terri Anna Perine Sarcoma Fund, the University of Utah Department of Pediatrics and Huntsman Cancer Institute/Huntsman Cancer Foundation. S.L.L. also acknowledges support to the Huntsman Cancer Institute (grant P30 CA042014). We would like to thank our reviewers for suggesting changes that allowed for a more comprehensive review of the

References (145)

R. Janknecht
EWS-ETS oncoproteins: the linchpins of Ewing tumors
Gene
(2005)
C.A. Stiller et al.
Bone tumours in European children and adolescents, 1978-1997. Report from the Automated Childhood Cancer Information System project
Eur J Cancer
(2006)
C. Kimber et al.
Primitive neuroectodermal tumours: anatomic location, extent of surgery, and outcome
J Pediatr Surg
(1998)
H.E. Grier
The Ewing family of tumors. Ewing’s sarcoma and primitive neuroectodermal tumors
Pediatr Clin North Am
(1997)
C. Turc-Carel et al.
Chromosome study of Ewing’s sarcoma (ES) cell lines. Consistency of a reciprocal translocation t(11;22)(q24;q12)
Cancer Genet Cytogenet
(1984)
C. Turc-Carel et al.
Chromosomes in Ewing’s sarcoma. I. An evaluation of 85 cases of remarkable consistency of t(11;22)(q24;q12)
Cancer Genet Cytogenet
(1988)
N. Araya et al.
Cooperative interaction of EWS with CREB-binding protein selectively activates hepatocyte nuclear factor 4-mediated transcription
J Biol Chem
(2003)
A. Hart et al.
Fli-1 is required for murine vascular and megakaryocytic development and is hemizygously deleted in patients with thrombocytopenia
Immunity
(2000)
L.A. Brown et al.
Insights into early vasculogenesis revealed by expression of the ETS-domain transcription factor Fli-1 in wild-type and mutant zebrafish embryos
Mech Dev
(2000)
A. Seth et al.
ETS transcription factors and their emerging roles in human cancer
Eur J Cancer
(2005)

R. Smith et al.

Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing’s sarcoma

Cancer Cell

(2006)

H. Kovar

Context matters: the hen or egg problem in Ewing’s sarcoma

Semin Cancer Biol

(2005)

P. Aman et al.

Expression patterns of the human sarcoma-associated genes FUS and EWS and the genomic structure of FUS

Genomics

(1996)

H.A. Chansky et al.

Targeting of EWS/FLI-1 by RNA interference attenuates the tumor phenotype of Ewing’s sarcoma cells in vitro

J Orthop Res

(2004)

E. Beauchamp et al.

GLI1 is a direct transcriptional target of EWS-FLI1 oncoprotein

J Biol Chem

(2009)

F. Nakatani et al.

Identification of p21WAF1/CIP1 as a direct target of EWS-Fli1 oncogenic fusion protein

J Biol Chem

(2003)

S.M. Welford et al.

DNA binding domain-independent pathways are involved in EWS/FLI1-mediated oncogenesis

J Biol Chem

(2001)

X. Mao et al.

The FLI-1 and chimeric EWS-FLI-1 oncoproteins display similar DNA binding specificities

J Biol Chem

(1994)

B.S. Braun et al.

Pediatric malignancies: update on sarcomas and leukemia development in children

Curr Opin Genet Dev

(2009)

F. Urano et al.

A novel chimera gene between EWS and E1A-F, encoding the adenovirus E1A enhancer-binding protein, in extraosseous Ewing’s sarcoma

Biochem Biophys Res Commun

(1996)

A. Verger et al.

Identification of amino acid residues in the ETS transcription factor Erg that mediate Erg-Jun/Fos-DNA ternary complex formation

J Biol Chem

(2001)

L. Wang et al.

Undifferentiated small round cell sarcomas with rare EWS gene fusions: identification of a novel EWS-SP3 fusion and of additional cases with the EWS-ETV1 and EWS-FEV fusions

J Mol Diagn

(2007)

T.L. Ng et al.

Ewing sarcoma with novel translocation t(2;16) producing an in-frame fusion of FUS and FEV

J Mol Diagn

(2007)

J. Ewing

Diffuse Endothelioma of Bone

Proceedings of the New York Pathological Society

(1921)

C.T. Denny

Ewing’s sarcoma–a clinical enigma coming into focus

J Pediatr Hematol Oncol

(1998)

M. Paulussen et al.

Ewing tumour: incidence, prognosis and treatment options

Paediatr Drugs

(2001)

Horowitz ME, Malawer MM, Woo SY, et al., Ewing’s Sarcoma Family of Tumors: Ewing’s Sarcoma of Bone and Soft Tissue and...

J. Whang-Peng et al.

Chromosome translocation in peripheral neuroepithelioma

N Engl J Med

(1984)

H. Kovar

Ewing’s sarcoma and peripheral primitive neuroectodermal tumors after their genetic union

Curr Opin Oncol

(1998)

P. Terrier et al.

Small round blue cell tumors in bone: prognostic factors correlated to Ewing’s sarcoma and neuroectodermal tumors

Semin Diagn Pathol

(1996)

C.C. Wang et al.

Ewing’s sarcoma; a study of fifty cases treated at the Massachusetts General Hospital, 1930-1952 inclusive

N Engl J Med

(1953)

D.C. Dahlin et al.

Ewing’s sarcoma. A critical analysis of 165 cases

J Bone Joint Surg Am

(1961)

M. Lahl et al.

Ewing’s sarcoma family of tumors: an overview from diagnosis to survivorship

Clin J Oncol Nurs

(2008)

R.L. Randall et al.

Is There a Predisposition Gene for Ewing’s Sarcoma?

J Oncol

(2010)

A.M. Linabery et al.

Childhood and adolescent cancer survival in the US by race and ethnicity for the diagnostic period 1975-1999

Cancer

(2008)

O. Delattre et al.

Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours

Nature

(1992)

A. Bertolotti et al.

EWS, but not EWS-FLI-1, is associated with both TFIID and RNA polymerase II: interactions between two members of the TET family, EWS and hTAFII68, and subunits of TFIID and RNA polymerase II complexes

Mol Cell Biol

(1998)

R. Petermann et al.

Oncogenic EWS-Fli1 interacts with hsRPB7, a subunit of human RNA polymerase II

Oncogene

(1998)

K.L. Rossow et al.

The Ewing’s sarcoma gene product functions as a transcriptional activator

Cancer Res

(2001)

F. Melet et al.

Generation of a novel Fli-1 protein by gene targeting leads to a defect in thymus development and a delay in Friend virus-induced erythroleukemia

Mol Cell Biol

(1996)

W.A. May et al.

Ewing sarcoma 11;22 translocation produces a chimeric transcription factor that requires the DNA-binding domain encoded by FLI1 for transformation

Proc Natl Acad Sci USA

(1993)

W.A. May et al.

The Ewing’s sarcoma EWS/FLI-1 fusion gene encodes a more potent transcriptional activator and is a more powerful transforming gene than FLI-1

Mol Cell Biol

(1993)

S.L. Lessnick et al.

Multiple domains mediate transformation by the Ewing’s sarcoma EWS/FLI- 1 fusion gene

Oncogene

(1995)

T. Ohno et al.

EWS/Fli-1 chimeric protein is a transcriptional activator

Cancer Res

(1993)

Y. Ben-David et al.

Erythroleukemia induction by Friend murine leukemia virus: insertional activation of a new member of the ets gene family, Fli-1, closely linked to c-ets-1

Genes Dev

(1991)

A.D. Sharrocks

The ETS-domain transcription factor family

Nat Rev Mol Cell Biol

(2001)

B.J. Graves et al.

Specificity within the ets family of transcription factors

Adv Cancer Res

(1998)

M. Ouchida et al.

Loss of tumorigenicity of Ewing’s sarcoma cells expressing antisense RNA to EWS-fusion transcripts

Oncogene

(1995)

H. Kovar et al.

EWS/FLI-1 antagonists induce growth inhibition of Ewing tumor cells in vitro

Cell Growth Differ

(1996)

K. Tanaka et al.

EWS-Fli1 antisense oligodeoxynucleotide inhibits proliferation of human Ewing’s sarcoma and primitive neuroectodermal tumor cells

J Clin Invest

(1997)

Cited by (191)

Sarcomas with EWSR1::Non-ETS Fusion (EWSR1::NFATC2 and EWSR1::PATZ1)
2024, Surgical Pathology Clinics
EWSR1::POU2AF3(COLCA2) Sarcoma: An Aggressive, Polyphenotypic Sarcoma With a Head and Neck Predilection
2023, Modern Pathology
EWSR1::POU2AF3 (COLCA2) sarcomas are a recently identified group of undifferentiated round/spindle cell neoplasms with a predilection for the head and neck region. Herein, we report our experience with 8 cases, occurring in 5 men and 3 women (age range, 37-74 years; median, 60 years). Tumors involved the head/neck (4 cases), and one each the thigh, thoracic wall, fibula, and lung. Seven patients received multimodal therapy; 1 patient was treated only with surgery. Clinical follow-up (8 patients; range, 4-122 months; median, 32 months) showed 5 patients with metastases (often multifocal, with a latency ranging from 7 to 119 months), and 3 of them also with local recurrence. The median local recurrence–free and metastasis-free survival rates were 24 months and 29 months, respectively. Of the 8 patients, 1 died of an unknown cause, 4 were alive with metastatic disease, 1 was alive with unresectable local disease, and 2 were without disease. The tumors were composed of 2 morphologic subgroups: (1) relatively bland tumors consisting of spindled to stellate cells with varying cellularity and fibromyxoid stroma (2 cases) and (2) overtly malignant tumors composed of nests of “neuroendocrine-appearing” round cells surrounded by spindled cells (6 cases). Individual cases in the second group showed glandular, osteogenic, or rhabdomyoblastic differentiation. Immunohistochemical results included CD56 (4/4 cases), GFAP (5/8), SATB2 (4/6), keratin (AE1/AE3) (5/8), and S100 protein (4/7). RNA sequencing identified EWSR1::POU2AF3 gene fusion in all cases. EWSR1 gene rearrangement was confirmed by fluorescence in situ hybridization in 5 cases. Our findings confirm the head/neck predilection and aggressive clinical behavior of EWSR1::POU2AF3 sarcomas and widen the morphologic spectrum of these rare lesions to include relatively bland spindle cell tumors and tumors with divergent differentiation.
Targeted long-read sequencing of the Ewing sarcoma 6p25.1 susceptibility locus identifies germline-somatic interactions with EWSR1-FLI1 binding
2023, American Journal of Human Genetics
Ewing sarcoma (EwS) is a rare bone and soft tissue malignancy driven by chromosomal translocations encoding chimeric transcription factors, such as EWSR1-FLI1, that bind GGAA motifs forming novel enhancers that alter nearby expression. We propose that germline microsatellite variation at the 6p25.1 EwS susceptibility locus could impact downstream gene expression and EwS biology. We performed targeted long-read sequencing of EwS blood DNA to characterize variation and genomic features important for EWSR1-FLI1 binding. We identified 50 microsatellite alleles at 6p25.1 and observed that EwS-affected individuals had longer alleles (>135 bp) with more GGAA repeats. The 6p25.1 GGAA microsatellite showed chromatin features of an EWSR1-FLI1 enhancer and regulated expression of RREB1, a transcription factor associated with RAS/MAPK signaling. RREB1 knockdown reduced proliferation and clonogenic potential and reduced expression of cell cycle and DNA replication genes. Our integrative analysis at 6p25.1 details increased binding of longer GGAA microsatellite alleles with acquired EWSR-FLI1 to promote Ewing sarcomagenesis by RREB1-mediated proliferation.
Ewing sarcoma genomics and recent therapeutic advancements
2023, Pediatric Hematology Oncology Journal
Ewing sarcomas are highly heterogenous mesenchymal tumors that develop in bone or soft tissue and primarily affect children, teenagers, and young adults. After osteosarcoma, it is the second most common malignant bone sarcoma. Ewing sarcoma, metastatic and relapsed, typically have a poor prognosis and recurrences are frequent, leading to high rates of morbidity and mortality. The ongoing inability to increase overall survival for patients with ewing sarcoma emphasizes the critical requirement for the quick translation of emerging therapy approaches. Targeting the EWR1/FLI1 fusion protein, which is the primary genetic anomaly and master regulator of Ewing sarcoma and found in 80–90% of instances of Ewing tumors, is the most crucial objective. This review offers new insights into the genomics and proteomics of Ewing sarcoma signaling and how it influences the tumor microenvironment and disease progression. It also elucidates how recent technological advancements have explained some of the underlying oncogenic characteristics of Ewing sarcoma. The current review examined existing and potential experimental therapies that, by enhancing patient survival and quality of life, target multiple signaling pathways involved in the progression of Ewing sarcoma. These therapies may one day replace current regimens as the new standard of care for patients.
Esophageal extraskeletal neoplasm Ewing's sarcoma: Case report
2022, International Journal of Surgery Case Reports
Ewing sarcomas are a group of small round cell tumors that occur predominantly in the long bones as well as in extraosseous locations such as the extremities, trunk, and retroperitoneum (Gier, 1997) [2]. Extraosseous Ewing sarcoma (EES) is a type of small round cell tumor that occurs in soft tissues. I rare cases, EES occurs in the esophagus (Maesawa et al., 2002; Johnson et al., 2010) [1,3]. Ewing's sarcoma is a rare and highly aggressive cancer most frequently arising in people under 20 years of age. We report an uncommon case of primary paraesophageal Ewing's sarcoma in a 25-year-old female.
A 26 years old Asian female referred primarily for surgical treatment due to esophageal cancer detected on her diagnostic investigations and revealed a primary tumor located near the gastroesophageal junction. Based on the results of diagnostic investigations which confirmed the possibility of the tumor Ewing sarcoma of esophagus, which was biopsy and immune histochemical stain proven the patient was qualified for surgical treatment. She underwent Mckewon esophagectomy on October 2021 for Ewing sarcoma of esophagus. She was first followed with neoadjuvant intravenous chemotherapy, after taking three cycles of neoadjuvant chemo showed good response in CT scan the patient underwent Mckewon esophagectomy, post op recovery was smooth she underwent 2 cycles of adjuvant chemotherapy after four months of surgery. Her followup visit was uneventful.
Ewing's sarcoma is the second most frequent primary malignant bone cancer, after osteosarcoma. It was first described by James Ewing in 1921, as an undifferentiated tumor developing in the diaphysis of the ulna of a young female patient (Ushigome et al., 2002) [6]. Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET), previously thought to be separate tumors, is now treated as the same tumor; both have similar immunohistochemical characteristics and chromosomal translocation (Maesawa et al., 2002) [1]. They are malignant tumors composed of undifferentiated small round cells, usually affecting children, adolescents, and young adults (Kondo et al., 2005) [7]. Generally ES/PNET affects the bones and deep soft tissues (Soulard et al., 2005) [8], although other organs such as the pancreas, small bowel, esophagus, kidneys, prostate, ovaries, vagina and rectovaginal septum have been reported; this is termed as extraskeletal ES/PNET (Bloom et al., 1995) [9]. To the best of our knowledge, only 5 cases of gastric ES/PNET have been reported in the English language literature.
Extraskeletal Ewing's sarcoma is a very rare disease, accounting for 6 %–47 % of all cases of Ewing's sarcoma. It is mainly diagnosed in the trunk, extremities, retroperitoneum, and head and neck region. Patients with extraosseous Ewing's sarcoma are more likely to be older, female, and not of Caucasian origin. An extraskeletal origin of the disease is correlated to poor prognosis (Siegel et al., 1988; Granowetter and West, 1997; Ushigome et al., 2002) [[4], [5], [6]]. We present an uncommon case of extraskeletal Ewing's sarcoma, and discuss its rare presentation and evolution. To our knowledge, this is the first reported case of paraesophageal primary Ewing's sarcoma and primitive neuroectodermal tumor.
Adenocarcinoma and squamous cell carcinoma account for the vast majority of esophageal malignancies. Other malignancies known to occur in the esophagus include melanoma, sarcoma, and lymphoma. Among the sarcomas, carcinosarcoma is the commonest with both carcinomatous and sarcomatous elements followed by leiomyosarcoma of mesenchymal origin. Other sarcomas reported in the literature are liposarcoma, synovial sarcoma, myxofibrosarcoma, Ewing's sarcoma, granulocytic sarcoma, histiocytic sarcoma, schwannoma rhabdomyosarcoma, and epithelioid sarcoma.
Ewing sarcoma is a rare entity among all esophageal malignancies. It presents as an exophytic mass, and in this case, it has presented as a mass occluding the lumen of esophagus. Most of these tumors present in locally advanced and disseminated condition, one of the reasons being difficulty and hence delay in diagnosis. In spite of best efforts, a group among them remains to be histologically uncharacterized.
Combinatorial strategies to potentiate the efficacy of HDAC inhibitors in fusion-positive sarcomas
2022, Biochemical Pharmacology
Citation Excerpt :
Upon chromosomal translocation, the ETS binding domain of FLI1 undergoes a conformational change which allows activation of a wider repertoire of genes with respect to the wt protein [34–36]. Through the aberrant conjugation of partners’ activities and neomorphic functions, EWS-FLI1 oncoproteins heavily impact transcription and splicing mechanisms causing a massive rewiring of the transcriptome and a widespread reprogramming of the epigenome [7,21,28,36–38]. By binding DNA at either ETS-like sequences that contain GGAA motif or at GGAA microsatellites, the oncoproteins act as potent transcriptional activators [39].
Fusion positive (FP) sarcomas are characterized by chromosomal rearrangements generating pathognomonic fusion transcripts and oncoproteins. In Ewing’s sarcoma family of tumors (ESFTs), FP-rhabdomyosarcomas (FP-RMS) and synovial sarcomas (SS), the most common and aggressive forms of sarcomas in childhood and adolescence, the oncogenic rearrangements involve transcription cofactors causing widespread epigenetic rewiring and aberrant gene expression. Through the cooperation with histone deacetylases (HDACs) in transcription regulatory complexes, the fusion oncoproteins affect histone acetylation and chromatin remodeling. The participation of HDACs in core mechanisms of sarcoma cell transformation has paved the way to the investigation of HDAC inhibitors (HDACis) for therapeutic intervention. Preclinical studies have provided convincing evidence that HDAC activity abrogation can revert malignant cell features driven by FET-ETS, PAX3/7-FOXO1 or SS18-SSX fusion oncogenes in ESFTs, FP-RMS, or SS models, respectively, resulting in in vitro and in vivo growth inhibition. While clinical trials of HDACi monotherapies led to drug approval in some hematologic malignancies, no significant therapeutic benefit has been reported in solid tumors, including sarcomas. HDACi-based combination therapies with targeted or conventional anticancer agents have shown limited efficacy in early studies recruiting sarcoma patients, although partial responses and disease stabilization have been reported. In these trials, sarcomas were represented, however, as unclassified group in most cases. We summarize, here, studies addressing the role of HDACs in FP-sarcoma pathobiology and HDACi-based rational drug combinations. Finally, we discuss the opportunity of exploiting drug inhibitory profile and expression/function of specific HDAC isoenzymes to harness the full therapeutic potential of HDACis in these sarcoma histotypes.

View all citing articles on Scopus

View full text

ReviewPromiscuous partnerships in Ewing's sarcoma

Section snippets

The EWS/FLI fusion in Ewing’s sarcoma

EWS/FLI fusion subtypes

Other EWS/ETS fusions in Ewing’s sarcoma

TET/ETS fusions in Ewing’s sarcoma

EWS/NFATc2

Cell-of-origin and cellular context in Ewing’s sarcoma

Potential mechanisms of chromosomal translocations in Ewing’s sarcoma

Is it time to revisit the concept that TET/ETS fusions are pathognomonic for Ewing’s sarcoma?

Should we care if non-TET/ETS-containing tumors are Ewing’s sarcoma?

Summary and conclusions

Acknowledgments

Gene

Eur J Cancer

J Pediatr Surg

Pediatr Clin North Am

Cancer Genet Cytogenet

Cancer Genet Cytogenet

J Biol Chem

Immunity

Mech Dev

Eur J Cancer

Cancer Cell

Semin Cancer Biol

Genomics

J Orthop Res

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Curr Opin Genet Dev

Biochem Biophys Res Commun

J Biol Chem

J Mol Diagn

J Mol Diagn

Diffuse Endothelioma of Bone

Proceedings of the New York Pathological Society

Ewing’s sarcoma–a clinical enigma coming into focus

J Pediatr Hematol Oncol

Ewing tumour: incidence, prognosis and treatment options

Paediatr Drugs

Chromosome translocation in peripheral neuroepithelioma

N Engl J Med

Ewing’s sarcoma and peripheral primitive neuroectodermal tumors after their genetic union

Curr Opin Oncol

Small round blue cell tumors in bone: prognostic factors correlated to Ewing’s sarcoma and neuroectodermal tumors

Semin Diagn Pathol

Ewing’s sarcoma; a study of fifty cases treated at the Massachusetts General Hospital, 1930-1952 inclusive

N Engl J Med

Ewing’s sarcoma. A critical analysis of 165 cases

J Bone Joint Surg Am

Ewing’s sarcoma family of tumors: an overview from diagnosis to survivorship

Clin J Oncol Nurs

Is There a Predisposition Gene for Ewing’s Sarcoma?

J Oncol

Childhood and adolescent cancer survival in the US by race and ethnicity for the diagnostic period 1975-1999

Cancer

Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours

Nature

EWS, but not EWS-FLI-1, is associated with both TFIID and RNA polymerase II: interactions between two members of the TET family, EWS and hTAFII68, and subunits of TFIID and RNA polymerase II complexes

Mol Cell Biol

Oncogenic EWS-Fli1 interacts with hsRPB7, a subunit of human RNA polymerase II

Oncogene

The Ewing’s sarcoma gene product functions as a transcriptional activator

Cancer Res

Generation of a novel Fli-1 protein by gene targeting leads to a defect in thymus development and a delay in Friend virus-induced erythroleukemia

Mol Cell Biol

Ewing sarcoma 11;22 translocation produces a chimeric transcription factor that requires the DNA-binding domain encoded by FLI1 for transformation

Proc Natl Acad Sci USA

The Ewing’s sarcoma EWS/FLI-1 fusion gene encodes a more potent transcriptional activator and is a more powerful transforming gene than FLI-1

Mol Cell Biol

Multiple domains mediate transformation by the Ewing’s sarcoma EWS/FLI- 1 fusion gene

Oncogene

EWS/Fli-1 chimeric protein is a transcriptional activator

Cancer Res

Erythroleukemia induction by Friend murine leukemia virus: insertional activation of a new member of the ets gene family, Fli-1, closely linked to c-ets-1

Genes Dev

The ETS-domain transcription factor family

Nat Rev Mol Cell Biol

Review
Promiscuous partnerships in Ewing's sarcoma