Investigations of menin function in Ewing sarcoma

尤文肉瘤中menin功能的研究

• 批准号: 10241553
• 负责人: Elizabeth R Lawlor
• 金额: $ 52.16万
• 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/10241553
• 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; MLL-rearranged leukemia; 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.

项目摘要 儿童癌症可以被认为是发育障碍，其中致癌驱动因子劫持了正常的 促进肿瘤发生的发展计划。支架蛋白menin对于正常的 在人类癌症中，它可以作为肿瘤抑制基因或癌基因发挥作用，具体取决于 上下文menin的多种功能与其通过其在基因转录调节中的作用有关。 与MLL组蛋白甲基转移酶的相互作用，以及与其他上下文依赖性结合配偶体。在 MLL重排白血病（MLLR），蛋白质：menin和MLL融合蛋白之间的蛋白质相互作用驱动 致癌转录程序的表观遗传激活。MLLR白血病的关键依赖于这些 相互作用代表了一种独特的治疗脆弱性和小分子抑制剂的menin：MLL 正在开发用于白血病定向治疗的相互作用。尤文肉瘤是一种间叶性肿瘤， 推测的干细胞（MSC）起源由EWS/ETS融合驱动，最常见的是EWS/FLI 1。EWS/FLI 1 通过劫持正常MSC分化启动肉瘤发生。重要的是，menin在以下方面发挥着重要作用： 早期间充质发育，在那里它有助于谱系定型和成骨细胞 分化我们已经证明，相对于MSC，尤文肉瘤过度表达menin， menin导致致瘤性丧失。然而，menin发挥其致癌作用的机制 在这些肿瘤细胞中的作用仍然未知。我们的初步数据确定了丝氨酸合成途径 (SSP)作为尤文肉瘤中menin的关键下游靶点。我们已经确认SSP是超- 在尤文肉瘤中以脑膜依赖性方式激活，而PHGDH的抑制， SSP中的酶，导致尤因肉瘤活力的严重丧失，揭示了尤因肉瘤的关键依赖性， 肉瘤的途径。我们的数据还表明，EWS/FLI 1本身有助于PHGDH的激活， SSP和EWS/FLI 1诱导靶亚组的转录依赖于menin。这些数据 共同支持menin在尤文肉瘤中作为致癌枢纽发挥作用的假设。在这 建议，我们将调查menin功能的机制，并测试创新的假设， EWS/FLI 1通过劫持脑膜依赖性转录调控促进肿瘤发生在目标1中， 确定menin激活SSP的机制，并阐明EWS/FLI 1在此过程中的作用。 过程在目标2中，我们将定义SSP的关键代谢物，这些代谢物有助于肿瘤维持， 以确定尤文肉瘤细胞为何如此依赖这一通路。目标3将定义全基因组 MSC和尤文肉瘤中menin的转录靶点以及它们如何受到EWS/FLI 1的影响。的 拟议的研究将推进尤文肉瘤生物学基础的基础知识， 发现EWS/FLI 1如何劫持正常的menin生理学以促进肿瘤发生。这些见解的目标是 将为尤文肉瘤开发新的、毒性较小的脑膜炎导向疗法提供机会。