Investigations of menin function in Ewing sarcoma

尤文肉瘤中menin功能的研究

• 批准号: 10190642
• 负责人: Elizabeth R Lawlor
• 金额: $ 56.17万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190642
• 关键词: Adolescence; Advanced Development; Binding; Biological; Biological Assay; Bone Development; Cells; Chimeric Proteins; Connective and Soft Tissue Neoplasm; DNA; Data; Dependence; Development; Enzymes; Epigenetic Process; Ewings sarcoma; FLI1 gene; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genetic study; Goals; Histones; Homeostasis; Human; Investigation; Knowledge; Lead; Link; Maintenance; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Menin; Mesenchymal; Mesenchymal Cell Neoplasm; Mesenchymal Stem Cells; Metabolic; Metabolic Pathway; Methyltransferase; Oncogenes; Oncogenic; Oxidation-Reduction; Pathogenesis; Pathway interactions; Pharmacology; Phenotype; Physiological; Physiology; Play; Process; RNA; Regulation; Role; Scaffolding Protein; Serine; Testing; Therapeutic; Tissues; Transcriptional Activation; Transcriptional Regulation; Tumor Suppressor Proteins; Tumorigenicity; cancer type; cofactor; developmental disease; epigenome; gene repression; genome-wide; histone methylation; histone methyltransferase; innovation; insight; leukemia; metabolomics; neoplastic cell; novel; nucleotide metabolism; osteoblast differentiation; overexpression; programs; promoter; protein protein interaction; small molecule inhibitor; stem cell differentiation; stem cells; therapeutic development; transcriptome; tumor; tumor initiation; tumorigenesis; tumorigenic

PROJECT SUMMARY Pediatric cancers can be considered developmental disorders in which oncogenic drivers hijack normal developmental programs to promote tumorigenesis. The scaffolding protein menin is essential for normal development and, in human cancer, can function as a tumor suppressor or an oncogene, depending on context. The diverse functions of menin are linked to its role in regulation of gene transcription via its interaction with MLL histone methyltransferases, as well as with other context-dependent binding partners. In MLL-rearranged leukemia (MLLr), protein:protein interactions between menin and MLL-fusion proteins drive epigenetic activation of oncogenic transcription programs. A critical dependence of MLLr leukemia on these interactions represents a unique therapeutic vulnerability and small molecule inhibitors of the menin:MLL interaction are being developed for leukemia-directed therapy. Ewing sarcomas are mesenchymal tumors of presumed stem cell (MSC) origin that are driven by EWS/ETS fusions, most commonly EWS/FLI1. EWS/FLI1 initiates sarcomagenesis by hijacking normal MSC differentiation. Importantly, menin plays an essential role in early mesenchymal development, where it contributes to both lineage commitment and osteoblastic differentiation. We have shown that menin is over-expressed by Ewing sarcoma relative to MSC and that loss of menin results in loss of tumorigenicity. However, the mechanisms by which menin exerts its oncogenic effects in these tumor cells remain unknown. Our preliminary data identified the serine synthesis pathway (SSP) as a key downstream target of menin in Ewing sarcoma. We have confirmed that the SSP is hyper- activated in Ewing sarcoma in a menin-dependent manner, and that inhibition of PHGDH, the rate limiting enzyme in the SSP, results in profound loss of Ewing sarcoma viability, revealing a key dependence of Ewing sarcoma on the pathway. Our data also suggest that EWS/FLI1 itself contributes to activation of PHGDH and the SSP, and that transcription of a subset of EWS/FLI1-induced targets is dependent on menin. These data collectively support the hypothesis that menin functions as an oncogenic hub in Ewing sarcoma. In this proposal, we will investigate the mechanisms of menin function and test the innovative hypothesis that EWS/FLI1 promotes tumorigenesis by hijacking menin-dependent transcriptional regulation. In Aim 1 we will determine the mechanism by which menin activates the SSP and will elucidate the role of EWS/FLI1 in this process. In Aim 2 we will define the key metabolites of the SSP that contribute to tumor maintenance in order to determine why Ewing sarcoma cells are so dependent on this pathway. In Aim 3 will define genome-wide transcriptional targets of menin in MSC and Ewing sarcoma and how they are impacted by EWS/FLI1. The proposed studies will advance fundamental knowledge of the biologic underpinnings of Ewing sarcoma and discover how EWS/FLI1 hijacks normal menin physiology to promote oncogenesis. It is goal that these insights will provide opportunities to develop novel, and less toxic, menin-directed therapies for Ewing sarcoma.

项目总结