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 儿科癌症可以认为是发育障碍，其中致癌驱动因素劫持了正常 促进肿瘤发生的发展计划。脚手架蛋白梅宁对于正常 发育，在人类癌症中，可以作为肿瘤抑制剂或癌基因起作用，具体取决于 语境。 Menin的各种功能与其在基因转录调节中的作用有关 与MLL组蛋白甲基转移酶以及其他依赖上下文依赖性结合伙伴的相互作用。在 MLL重新培养白血病（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白血病对这些的关键依赖性 相互作用代表了一个独特的治疗脆弱性和小分子抑制剂：MLL 正在开发用于白血病定向治疗的相互作用。尤因肉瘤是间充质肿瘤 由EWS/ETS融合驱动的假定干细胞（MSC）起源，最常见的是EWS/FLI1。 EWS/FLI1 通过劫持正常的MSC分化来启动肌动症。重要的是，梅宁在 早期的间充质发育，在那里有助于谱系承诺和成骨细胞 分化。我们已经表明，梅宁相对于MSC而被EWING SARMA所表达过多，而损失 梅宁导致肿瘤性丧失。但是，Menin发挥其致癌的机制 这些肿瘤细胞的影响仍然未知。我们的初步数据确定了丝氨酸合成途径 （SSP）是埃温肉瘤中Menin的关键下游目标。我们已经确认SSP是超级 以梅宁依赖性的方式激活ewing肉瘤，并抑制pHGDH，速率限制 SSP中的酶，导致肉瘤生存能力的巨大丧失，揭示了尤因的关键依赖性 肉瘤在小路上。我们的数据还表明，EWS/FLI1本身有助于PHGDH的激活和 SSP以及EWS/FLI1诱导的靶标子集的转录取决于Menin。这些数据 共同支持了Menin在Ewing肉瘤中充当致癌中心的假设。在这个 提案，我们将研究Menin功能的机制，并检验创新的假设 EWS/FLI1通过劫持Menin依赖性转录调控来促进肿瘤发生。在目标1中，我们将 确定Menin激活SSP的机制，并将阐明EWS/FLI1在此中的作用 过程。在AIM 2中，我们将定义SSP的关键代谢产物，该代谢有助于肿瘤维持的顺序 确定为什么尤因肉瘤细胞如此依赖于此途径。在AIM 3中将定义全基因组 Menin在MSC和EWING肉瘤中的转录靶标，以及它们如何受到EWS/FLI1的影响。这 拟议的研究将促进对尤因肉瘤和的生物基础的基本知识 发现EWS/FLI1如何劫持正常的Menin生理学来促进肿瘤发生。这些见解是目标 将为开发ewing肉瘤的新颖且毒性较小的梅宁指导疗法提供机会。