Ewing’s sarcoma precursors are highly enriched in embryonic osteochondrogenic progenitors

Abstract

Ewing's sarcoma is a highly malignant bone tumor found in children and adolescents, and the origin of this malignancy is not well understood. Here, we introduced a Ewing's sarcoma-associated genetic fusion of the genes encoding the RNA-binding protein EWS and the transcription factor ETS (EWS-ETS) into a fraction of cells enriched for osteochondrogenic progenitors derived from the embryonic superficial zone (eSZ) of long bones collected from late gestational murine embryos. EWS-ETS fusions efficiently induced Ewing's sarcoma-like small round cell sarcoma formation by these cells. Analysis of the eSZ revealed a fraction of a precursor cells that express growth/differentiation factor 5 (Gdf5), the transcription factor Erg, and parathyroid hormone-like hormone (Pthlh), and selection of the Pthlh-positive fraction alone further enhanced EWS-ETSdependent tumor induction. Genes downstream of the EWS-ETS fusion protein were quite transcriptionally active in eSZ cells, especially in regions in which the chromatin structure of the ETS-responsive locus was open. Inhibition of β-catenin, poly (ADP-ribose) polymerase 1 (PARP1), or enhancer of zeste homolog 2 (EZH2) suppressed cell growth in a murine model of Ewing's sarcoma, suggesting the utility of the current system as a preclinical model. These results indicate that eSZ cells are highly enriched in precursors to Ewing's sarcoma and provide clues to the histogenesis of Ewing's sarcoma in bone.

MEIS1-mediated transactivation of synaptotagmin-like 1 promotes CXCL12/CXCR4 signaling and leukemogenesis

“…Mice were monitored daily for evidence of disease, and smears of peripheral blood were examined every week. The onset of AML was determined by detecting when immature myeloid cells constituted at least 20% of the leukoences in transcriptional regulation between normal and neoplastic cells might be caused by alterations in chromatin conditions at target loci (56). In contrast, known target genes of MEIS1, such as Msi2 (20) and Hif1a (21), were also identified in the present study (Supplemental Table 3).…”

EWS-FLI1 Utilizes Divergent Chromatin Remodeling Mechanisms to Directly Activate or Repress Enhancer Elements in Ewing Sarcoma

“…It is worth noting that, while the lack of conservation of repeat sites suggests limitations for modeling EWS-FLI1 mediated events in other organisms, the ability of the fusion protein to act as a pioneer factor may result in the activation of different GGAA repeats near locations corresponding to EWS-FLI1 binding sites in humans. It is thus possible that appropriately localized GGAA repeats may allow EWS-FLI1 to regulate some fraction of its target gene repertoire in other species (Tanaka et al, 2014). In contrast to activation, the direct repression of enhancers by EWS-FLI1 occurs at non-repeat canonical ETS binding sites that display strong evolutionary conservation and regulatory activity in other cell types.…”

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

“…For the analysis of in vivo metastatic potential 2x10 6 ES cells were injected in a volume of 0.2ml into the tail vein of immunodeficient Rag2 -/-γ C -/-mice. Five weeks later mice were sacrificed and metastatic spread was monitored in individual organs.…”

“…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].…”