fli1 antibody, Targeting CD99 compromises the oncogenic effects of the chimera EWS-FLI1 by inducing re-expression of zyxin and inhibition of Gli1 activity

Targeting CD99 compromises the oncogenic effects of the chimera EWS-FLI1 by inducing re-expression of zyxin and inhibition of Gli1 activity

Ewing sarcoma (EWS), a highly aggressive pediatric tumor, is driven by EWS-FLI1, an oncogenic transcription factor that remodels the tumor genetic landscape. Epigenetic mechanisms play a pivotal role in EWS pathogenesis, and the therapeutic value of compounds targeting epigenetic pathways is being identified in preclinical models. Here we showed that modulation of CD99, a cell surface molecule highly expressed in EWS cells, may alter transcriptional dysregulation in EWS through control of the zyxin-Gli1 axis.
Zyxin is transcriptionally repressed, but Gli1 expression is maintained by EWS-FLI1. We demonstrated that targeting CD99 with antibodies, including the human diabody C7, or genetically inhibiting CD99 is sufficient to increase zyxin expression and induce its dynamic nuclear accumulation.
Nuclear zyxin functionally affects Gli1, inhibiting targets such as NKX2-2, cyclin D1, and PTCH1 and upregulating GAS1, a tumor suppressor protein negatively regulated by Shh/Gli1 signaling We used a battery of functional assays to demonstrate: a) the relationship between CD99/zyxin and tumor cell growth/migration and; b) how CD99 deprivation from the EWS cell surface is sufficient to specifically affect the expression of some crucial EWS-FLI1 targets, both in vitro and in vivo, even in the presence of EWS-FLI1This work reveals that the CD99/zyxin/Gli1 axis is promising therapeutic target for reducing EWS malignancy.

Current Status of Management and Outcome for Patients with Ewing Sarcoma

Ewing sarcoma is the second most common bone sarcoma in children after osteosarcoma. It is a very aggressive malignancy for which systemic treatment has greatly improved outcome for patients with localized disease, who now see survival rates of over 70%. However, for the quarter of patients presenting with metastatic disease, survival is still dismal with less than 30% of patients surviving past 5 years. Patients with disease relapse, local or distant, face an even poorer prognosis with an event-free 5-year survival rate of only 10%.
Unfortunately, Ewing sarcoma patients have not yet seen the benefit of recent years’ technical achievements such as next-generation sequencing, which have enabled researchers to study biological systems at a level never seen before. In spite of large multinational studies, treatment of Ewing sarcoma relies entirely on chemotherapeutic agents that have been largely unchanged for decades.
As many promising modern therapies, including monoclonal antibodies, small molecules, and immunotherapy, have been disappointing to date, there is no clear candidate as to which drug should be investigated in the next large-scale clinical trial. However, the mechanisms driving tumor development in Ewing sarcoma are slowly unfolding.
New entities of Ewing-like tumors, with fusion transcripts that are related to the oncogenic EWSR1-FLI1 fusion seen in the majority of Ewing tumors, are being mapped. These tumors, although sharing much of the same morphologic features as classic Ewing sarcoma, behave differently and may require a different treatment. There are also controversies regarding local treatment of Ewing sarcoma. The radiosensitive nature of the disease and the tendency for Ewing sarcoma to arise in the axial skeleton make local treatment very challenging.
Surgical treatment and radiotherapy have their pros and cons, which may give rise to different treatment strategies in different centers around the world. This review article discusses some of these controversies and reproduces the highlights from recent publications with regard to diagnostics, systemic treatment, and surgical treatment of Ewing sarcoma.

Regulation of MHC class I-independent NK cell education by SLAM family receptors.

Seven members of signaling lymphocytic activation molecule (SLAM) family receptors (SFRs) are ubiquitously expressed on hematopoietic cells and they play critical roles in immune cell differentiation and activation. The engagement of these receptors transmits intracellular signaling mainly by recruiting SLAM-associated protein (SAP) and its related adaptors, EWS-FLI1-activated transcript-2 (EAT-2) and EAT-2-related transducer (ERT).
The critical roles of SFRs and SAP-family adaptors are highlighted by the discovery that SAP is mutated in human X-linked lymphoproliferative (XLP1) disease in which the contact between T and B cells in germinal center and cytotoxic lymphocytes (NK cells and CD8+ T cells) function are severely compromised. These immune defects are closely associated with the defective antibody production and the high incidence of lymphoma in the patients with XLP1.
In addition to these well-known functions, SLAM-SAP family is involved in NK cell education, a process describing NK cell functional competence. In this chapter, we will mainly discuss these unappreciated roles of SAP-dependent and SAP-independent SFR signaling in regulating MHC-I-independent NK cell education.

Size-based detection of sarcoma circulating tumor cells and cell clusters.

Metastatic disease is the most important factor in determining the survival of sarcoma patients. Since sarcoma metastasis is predominantly hematogenous, we hypothesized that detection and quantification of circulating tumor cells (CTCs) could reflect response to therapy and risk of metastatic relapse. We evaluated the presence of CTCs using a novel animal model and in the blood of patients with high grade sarcomas utilizing the CellSieve™ size-based low pressure microfiltration system.
fli1 antibody, Targeting CD99 compromises the oncogenic effects of the chimera EWS-FLI1 by inducing re-expression of zyxin and inhibition of Gli1 activity
Sarcoma CTCs were identified based on antibody staining patterns and nuclear morphology. Additionally, RNA was extracted from the CTCs for molecular analysis including demonstration of an EWS-FLI1 translocation, identification of a previously unrecognized p53 mutation in a patient with Ewing sarcoma, and single cell RNA sequencing of CTC from a child with alveolar rhabdomyosarcoma.
In mouse xenograft models, the presence of CTC correlates with disease burden and with clinically silent metastases. In human patients, CTCs were readily detected at diagnosis, decreased with successful treatment, and were detectable in the blood of patients with no radiographic evidence of disease prior to the development of overt metastasis.
Although evaluation of CTC is established in the care of patients with carcinomas, this technology has yet to be effectively applied to the evaluation and treatment of sarcoma patients. Our work demonstrates that the CellSieve™ microfiltration system can be used to study the biology of CTC in both mouse models and human sarcoma patients, with the potential for application to the monitoring of disease response and prediction of metastatic relapse.

Potential approaches to the treatment of Ewing’s sarcoma.

Ewing’s sarcoma (ES) is a highly aggressive and metastatic tumor in children and young adults caused by a chromosomal fusion between the Ewing sarcoma breakpoint region 1 (EWSR1) gene and the transcription factor FLI1 gene. ES is managed with standard treatments, including chemotherapy, surgery and radiation. Although the 5-year survival rate for primary ES has improved, the survival rate for ES patients with metastases or recurrence remains low.
Several novel molecular targets in ES have recently been identified and investigated in preclinical and clinical settings, and targeting the function of receptor tyrosine kinases (RTKs), the fusion protein EWS-FLI1 and mTOR has shown promise. There has also been increasing interest in the immune responses of ES patients. Immunotherapies using T cells, NK cells, cancer vaccines and monoclonal antibodies have been considered for ES, especially for recurrent patients.

FLI1 Antibody

AF0161 200ul
EUR 420

FLI1 Antibody

1-CSB-PA897216
  • EUR 380.40
  • EUR 292.80
  • 100ul
  • 50ul
Description: A polyclonal antibody against FLI1. Recognizes FLI1 from Human, Mouse. This antibody is Unconjugated. Tested in the following application: ELISA, WB;ELISA:1:1000-1:2000, WB:1:200-1:1000

FLI1 antibody

70R-49751 100 ul
EUR 292.8
Description: Purified Polyclonal FLI1 antibody

FLI1 Antibody

7449-002mg 0.02 mg
EUR 206.18
Description: The Friend leukemia virus integration 1 (FLI1) protein is a transcription factor containing an ETS DNA-binding domain and is highly expressed in hematopoietic cell lineages and vascular endothelial cells (1). FLI1 plays important roles in megakaryocytic differentiation (2) and vascular homeostasis (3). The FLI1 gene can undergo a t(11;22)(q24;q12) translocation with the Ewing sarcoma gene on chromosome 22, which results in a fusion gene that is present in the majority of Ewing sarcoma cases. (4). Abnormal expression of FLI1 can be used as an adverse prognostic indicator for acute myeloid leukemia (5).

FLI1 Antibody

7449-01mg 0.1 mg
EUR 523.7
Description: The Friend leukemia virus integration 1 (FLI1) protein is a transcription factor containing an ETS DNA-binding domain and is highly expressed in hematopoietic cell lineages and vascular endothelial cells (1). FLI1 plays important roles in megakaryocytic differentiation (2) and vascular homeostasis (3). The FLI1 gene can undergo a t(11;22)(q24;q12) translocation with the Ewing sarcoma gene on chromosome 22, which results in a fusion gene that is present in the majority of Ewing sarcoma cases. (4). Abnormal expression of FLI1 can be used as an adverse prognostic indicator for acute myeloid leukemia (5).

FLI1 antibody

70R-31192 100 ug
EUR 392.4
Description: Rabbit polyclonal FLI1 antibody

FLI1 Antibody

43320-100ul 100ul
EUR 302.4

FLI1 antibody

70R-17319 50 ul
EUR 522
Description: Rabbit polyclonal FLI1 antibody

FLI1 Antibody

21433-100ul 100ul
EUR 302.4

FLI1 Antibody

21433-50ul 50ul
EUR 224.4

FLI1 antibody

20R-2505 50 ug
EUR 337.2
Description: Rabbit polyclonal FLI1 antibody

FLI1 Antibody

33376-100ul 100ul
EUR 302.4

FLI1 Antibody

33376-50ul 50ul
EUR 224.4

FLI1 Antibody

32943-100ul 100ul
EUR 302.4

FLI1 Antibody

ABD7434 100 ug
EUR 525.6

FLI1 Antibody

ABF0161 100 ug
EUR 525.6

FLI1 Antibody

R31300 100 ug
EUR 419

FLI1 Antibody

V8430-100UG 100 ug
EUR 499
Description: Recognizes a protein of 51kDa, which is identified as FLI1. This protein, a member of the ETS family of DNA binding transcription factors, is involved in cellular proliferation and tumorigenesis. Ets-1 is the prototype member of a family of genes identified on the basis of homology to the v-Ets oncogene isolated from the E26 erythroblastosis virus. Members of the Ets gene family share a highly conserved carboxy-terminal domain containing a sequence related to the SV40 large T antigen nuclear localization signal sequence. Approximately 90% of Ewings Sarcomas. High sensitivity and specificity of Fli-1 equals to or exceeds that of the established vascular markers like CD31, CD34, and Factor VIII.

FLI1 Antibody

V8430-20UG 20 ug
EUR 219
Description: Recognizes a protein of 51kDa, which is identified as FLI1. This protein, a member of the ETS family of DNA binding transcription factors, is involved in cellular proliferation and tumorigenesis. Ets-1 is the prototype member of a family of genes identified on the basis of homology to the v-Ets oncogene isolated from the E26 erythroblastosis virus. Members of the Ets gene family share a highly conserved carboxy-terminal domain containing a sequence related to the SV40 large T antigen nuclear localization signal sequence. Approximately 90% of Ewings Sarcomas. High sensitivity and specificity of Fli-1 equals to or exceeds that of the established vascular markers like CD31, CD34, and Factor VIII.
Because understanding the pathogenesis of ES is extremely important for the development of novel treatments, this review focuses on the mechanisms and functions of targeted therapies and immunotherapies in ES. It is anticipated that integrating the knowledge obtained from basic research and translational and clinical studies will lead to the development of novel therapeutic strategies for the treatment of ES.

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