EWS/FLI

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EWS/FLI1 is an oncogenic protein that is pathognomonic for Ewing sarcoma. [1] It is found in approximately 90% of all Ewing sarcoma tumors with the remaining 10% of fusions substituting one fusion partner with a closely related family member (e.g. ERG for FLI1). [2]

Contents

Origin

EWSR1 is a gene on chromosome 22 whose mRNA is translated into the protein Ewing sarcoma breakpoint region 1 (abbreviated EWS). The gene FLI1 resides on chromosome 11 where it encodes a member of the ETS transcription factor family, Friend leukemia integration 1 transcription factor (abbreviated FLI1).

Most fusions between EWS and FLI1 result from a t(11;22)(q24;q12) reciprocal chromosome translocation. [3] This translocation creates a chimeric transcript which fuses exons 1-7 of EWSR1 to exons 6-9 (or less commonly 5-9) of FLI1. [4] [5]

It has recently been appreciated that almost half of EWS and FLI1 fusions are a result of chromoplexy. [6] Evidence of chromoplectic looping is enriched in both metastatic and p53 mutant tumors. Chromoplectic looping appears to be the mechanism involved in forming the EWS/ERG variant transcription factor. This preference is probably due to EWSR1 and ERG being in opposite orientations on the genome precluding the production of functional EWS/ERG via a reciprocal translocation.

Molecular Biology

EWS/FLI1 functions as both a pioneering transcription factor and potent oncogene. [7] Its expression leads to a complete restructuring of the transcriptome of the cell of origin to favor a tumorigenic state. EWS/FLI1 accomplishes this through a set of complementary mechanisms:

  1. The N-terminus of EWS/FLI1 retains the prion-like transactivation domain of EWSR1. This allows EWS/FLI1 to both bind RNA polymerase II and recruit the BAF complex. These interactions change heterochromatin to euchromatin at EWS/FLI1 DNA-binding sites effectively generating de novo enhancers. [8] [9]
  2. The C-terminus of EWS/FLI1 retains the DNA-binding domain of FLI1. While wild-type FLI1 recognizes an ACCGGAAG core sequence, [10] EWS/FLI1 preferentially binds GGAA-repetitive regions. There is a positive correlation between the number of consecutive GGAA microsatellites, EWS/FLI1 binding, and target gene expression. [11]
  3. The core motif of ETS transcription factors includes a GGAA sequence. EWS/FLI1 may bind to such sequences with greater affinity than the wild-type ETS member disrupting the normal regulation of ETS target genes. [12]

Related Research Articles

<span class="mw-page-title-main">Fusion gene</span>

A fusion gene is a hybrid gene formed from two previously independent genes. It can occur as a result of translocation, interstitial deletion, or chromosomal inversion. Fusion genes have been found to be prevalent in all main types of human neoplasia. The identification of these fusion genes play a prominent role in being a diagnostic and prognostic marker.

<span class="mw-page-title-main">Desmoplastic small-round-cell tumor</span> Aggressive and rare cancer

Desmoplastic small-round-cell tumor (DSRCT) is an aggressive and rare cancer that primarily occurs as masses in the abdomen. Other areas affected may include the lymph nodes, the lining of the abdomen, diaphragm, spleen, liver, chest wall, skull, spinal cord, large intestine, small intestine, bladder, brain, lungs, testicles, ovaries, and the pelvis. Reported sites of metastatic spread include the liver, lungs, lymph nodes, brain, skull, and bones. It is characterized by the EWS-WT1 fusion protein.

<span class="mw-page-title-main">Ewing sarcoma</span> Type of cancer

Ewing sarcoma is a type of cancer that forms in bone or soft tissue. Symptoms may include swelling and pain at the site of the tumor, fever, and a bone fracture. The most common areas where it begins are the legs, pelvis, and chest wall. In about 25% of cases, the cancer has already spread to other parts of the body at the time of diagnosis. Complications may include a pleural effusion or paraplegia.

<span class="mw-page-title-main">ETV6</span> Protein-coding gene in the species Homo sapiens

ETV6 protein is a transcription factor that in humans is encoded by the ETV6 gene. The ETV6 protein regulates the development and growth of diverse cell types, particularly those of hematological tissues. However, its gene, ETV6 frequently suffers various mutations that lead to an array of potentially lethal cancers, i.e., ETV6 is a clinically significant proto-oncogene in that it can fuse with other genes to drive the development and/or progression of certain cancers. However, ETV6 is also an anti-oncogene or tumor suppressor gene in that mutations in it that encode for a truncated and therefore inactive protein are also associated with certain types of cancers.

<span class="mw-page-title-main">MN1 (gene)</span> Protein-coding gene in the species Homo sapiens

MN1 is a gene found on human chromosome 22, with gene map locus 22q12.3-qter. Its official full name is meningioma 1 because it is disrupted by a balanced translocation (4;22) in a meningioma.

<span class="mw-page-title-main">NFATC2</span> Protein-coding gene in the species Homo sapiens

Nuclear factor of activated T-cells, cytoplasmic 2 is a protein that in humans is encoded by the NFATC2 gene.

<span class="mw-page-title-main">FLI1</span> Protein-coding gene in the species Homo sapiens

Friend leukemia integration 1 transcription factor (FLI1), also known as transcription factor ERGB, is a protein that in humans is encoded by the FLI1 gene, which is a proto-oncogene.

<span class="mw-page-title-main">ATF1</span> Protein-coding gene in humans

Cyclic AMP-dependent transcription factor ATF-1 is a protein that in humans is encoded by the ATF1 gene.

<span class="mw-page-title-main">ETV4</span> Protein-coding gene in the species Homo sapiens

ETS translocation variant 4 (ETV4), also known as polyoma enhancer activator 3 (PEA3), is a member of the PEA3 subfamily of Ets transcription factors.

<span class="mw-page-title-main">RNA-binding protein EWS</span> Human protein and coding gene

RNA-binding protein EWS is a protein that in humans is encoded by the EWSR1 gene on human chromosome 22, specifically 22q12.2. It is one of 3 proteins in the FET protein family. The q22.2 region of chromosome 22 encodes the N-terminal transactivation domain of the EWS protein and that region may become joined to one of several other chromosomes which encode various transcription factors, see and the FET protein family. The expression of a chimeric protein with the EWS transactivation domain fused to the DNA binding region of a transcription factor generates a powerful oncogenic protein causing Ewing sarcoma and other members of the Ewing family of tumors. These translocations can occur due to chromoplexy, a burst of complex chromosomal rearrangements seen in cancer cells. The normal EWS gene encodes an RNA binding protein closely related to FUS (gene) and TAF15, all of which have been associated to amyotrophic lateral sclerosis.

<i>ERG</i> (gene) Protein-coding gene in the species Homo sapiens

ERG is an oncogene. ERG is a member of the ETS family of transcription factors. The ERG gene encodes for a protein, also called ERG, that functions as a transcriptional regulator. Genes in the ETS family regulate embryonic development, cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis.

<span class="mw-page-title-main">RNA-binding protein FUS</span> Human protein and coding gene

RNA-binding protein FUS/TLS, also known as heterogeneous nuclear ribonucleoprotein P2 is a protein that in humans is encoded by the FUS gene.

<span class="mw-page-title-main">TAF15</span> Protein-coding gene in the species Homo sapiens

TATA-binding protein-associated factor 2N is a protein that in humans is encoded by the TAF15 gene.

The Ewing family of tumors (EFTs) is a group of small cell sarcomas including Ewing sarcoma of the bone, extra osseous Ewing tumors, and primitive neuroectodermal tumors. They are rare cancers, usually diagnosed in peoples' twenties. The sarcoma of bone is the most common of the variants. All forms are predisposed to metastasis and have had historically high rates of mortality. The family of tumors shares a common translocation mutation of the EWS gene on chromosome 22 to an ETS-type gene, most commonly the FLI1 gene. EFTs are highly malignant, with 5-year survival for patients with metastatic disease at 20%. The current standard of care includes resection, radiation, and chemotherapy.

<span class="mw-page-title-main">ETS transcription factor family</span> Protein family

In the field of molecular biology, the ETSfamily is one of the largest families of transcription factors and is unique to animals. There are 29 genes in humans, 28 in the mouse, 10 in Caenorhabditis elegans and 9 in Drosophila. The founding member of this family was identified as a gene transduced by the leukemia virus, E26. The members of the family have been implicated in the development of different tissues as well as cancer progression.

<span class="mw-page-title-main">Myxoid liposarcoma</span> Medical condition

A myxoid liposarcoma is a malignant adipose tissue neoplasm of myxoid appearance histologically.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare low-grade malignant mesenchymal neoplasm of the soft tissues, that differs from other sarcomas by unique histology and characteristic chromosomal translocations. There is an uncertain differentiation and neuroendocrine differentiation is even possible.

Chromoplexy refers to a class of complex DNA rearrangement observed in the genomes of cancer cells. This phenomenon was first identified in prostate cancer by whole genome sequencing of prostate tumors. Chromoplexy causes genetic material from one or more chromosomes to become scrambled as multiple strands of DNA are broken and ligated to each other in a new configuration. In prostate cancer, chromoplexy may cause multiple oncogenic events within a single cell cycle, providing a proliferative advantage to a (pre-)cancerous cell. Several oncogenic mutations in prostate cancer occur through chromoplexy, such as disruption of the tumor suppressor gene PTEN or creation of the TMPRSS2-ERG fusion gene.

Sclerosing epithelioid fibrosarcoma (SEF) is a very rare malignant tumor of soft tissues that on microscopic examination consists of small round or ovoid neoplastic epithelioid fibroblast-like cells, i.e. cells that have features resembling both epithelioid cells and fibroblasts. In 2020, the World Health Organization classified SEF as a distinct tumor type in the category of malignant fibroblastic and myofibroblastic tumors. However, current studies have reported that low-grade fibromyxoid sarcoma (LGFMS) has many clinically and pathologically important features characteristic of SEF; these studies suggest that LGSFMS may be an early form of, and over time progress to become, a SEF. Since the World Health Organization has classified LGFMS as one of the malignant fibroblastic and myofibroblastic tumors that is distinctly different than SEF, SEF and LGFMS are here regarded as different tumor forms.

The FET protein family the EWSR1 protein encoded by the EWSR1 gene located at band 12.2 of the long arm of chromosome 22; 2) the FUS protein encoded by the FUS gene located at band 16 on the short arm of chromosome 16; and 3) the TAF15 protein encoded by the TAF15 gene located at band 12 on the long arm of chromosome 7 The FET in this protein family's name derives form the first letters of FUS, EWSR1, and TAF15.

References

  1. ↑ Grünewald, TGP (July 5, 2018). "Ewing sarcoma". Nature Reviews Disease Primers. 4 (5): 5. doi:10.1038/s41572-018-0003-x. PMID   29977059. S2CID   49571421.
  2. ↑ Tirode, Franck (May 1, 2015). "Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations". Cancer Discovery. 4 (11): 1342–1353. doi:10.1158/2159-8290.CD-14-0622. PMC   4264969 . PMID   25223734.
  3. ↑ Downing, J. R. (November 1993). "Detection of the (11;22)(q24;q12) translocation of Ewing's sarcoma and peripheral neuroectodermal tumor by reverse transcription polymerase chain reaction". The American Journal of Pathology. 143 (5): 1294–1300. PMC   1887175 . PMID   8238248.
  4. ↑ Zucman, Jessica (November 1992). "Cloning and characterization of the Ewing's sarcoma and peripheral neuroepithelioma t(11;22) translocation breakpoints". Genes, Chromosomes & Cancer. 5 (4): 271–277. doi:10.1002/gcc.2870050402. PMID   1283315. S2CID   23718350.
  5. ↑ Grohar, Patrick (January 26, 2016). "Functional genomic screening reveals splicing of the EWS-FLI1 fusion transcript as a vulnerability in Ewing sarcoma". Cell Reports. 14 (3): 598–610. doi:10.1016/j.celrep.2015.12.063. PMC   4755295 . PMID   26776507.
  6. ↑ Anderson, Nathaniel D (February 28, 2019). "Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors". Science. 361 (6405): eaam8419. doi:10.1126/science.aam8419. PMC   6176908 . PMID   30166462.
  7. ↑ Riggi, Nicolò Riggi (April 2008). "EWS-FLI-1 Expression Triggers a Ewing's Sarcoma Initiation Program in Primary Human Mesenchymal Stem Cells". Cancer Research. 68 (7): 2176–85. doi: 10.1158/0008-5472.CAN-07-1761 . PMID   18381423.
  8. ↑ Boulay, Gaylor (21 September 2017). "Cancer-Specific Retargeting of BAF Complexes by a Prion-like Domain". Cell. 171 (1): 163–178. doi:10.1016/j.cell.2017.07.036. PMC   6791823 . PMID   28844694.
  9. ↑ Petermann, Robert (6 August 1998). "Oncogenic EWS-Fli1 interacts with hsRPB7, a subunit of human RNA polymerase II". Oncogene. 17 (5): 603–610. doi: 10.1038/sj.onc.1201964 . PMID   9704926.
  10. ↑ Mao, Xiaohong (8 July 1998). "The FLI-1 and Chimeric EWS-FLI-1Oncoproteins Display Similar DNA Binding Specificities". The Journal of Biological Chemistry. 269 (27): 18216–18222. doi: 10.1016/S0021-9258(17)32437-7 . PMID   7517940.
  11. ↑ Johnson, Kirsten (November 1, 2017). "Identification of two types of GGAA-microsatellites and their roles in EWS/FLI binding and gene regulation in Ewing sarcoma". PLOS ONE. 12 (11): e0186275. Bibcode:2017PLoSO..1286275J. doi: 10.1371/journal.pone.0186275 . PMC   5665490 . PMID   29091716.
  12. ↑ Riggi, Nicolò (October 30, 2014). "EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma". Cancer Cell. 26 (5): 668–681. doi:10.1016/j.ccell.2014.10.004. PMC   4492343 . PMID   25453903.
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