Regulation of Protein Synthesis in Leukemia Stem Cells

白血病干细胞中蛋白质合成的调控

• 批准号: 10801320
• 负责人: Stephen Shiu-Wah Chung
• 金额: $ 47.54万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10801320
• 关键词: Acute Myelocytic Leukemia; Address; Adopted; BCL2 gene; Biogenesis; Blood Cells; Cell surface; Cells; Clinic; Clinical; Complement; Dependence; Development; Disease; Evaluation; Exhibits; Gene Expression; Gene Mutation; Generations; Genetic; Genetically Engineered Mouse; Goals; Green Fluorescent Proteins; Hematopoietic stem cells; Human; Impairment; Knowledge; Link; Maintenance; Malignant Neoplasms; Measures; Mediating; Modeling; Molecular; Monoclonal Antibodies; Outcome; Patient-Focused Outcomes; Patients; Process; Protein Biosynthesis; Protein Synthesis Inhibition; Proteins; Recurrent disease; Regulation; Reporter; Research; Resistance; Ribosomal Proteins; Ribosomes; Role; Stress; System; Testing; Therapeutic; Toxic effect; Transcript; Translating; Translations; Tumor Suppressor Proteins; Work; Xenograft procedure; biological adaptation to stress; cancer stem cell; cytotoxicity; design; effective therapy; genetic manipulation; high risk; improved; in vivo; inhibitor; innovation; insight; leukemia; leukemic stem cell; mouse model; novel; novel therapeutic intervention; novel therapeutics; overexpression; patient derived xenograft model; prevent; progenitor; programs; proteotoxicity; response; ribosome profiling; self-renewal; stem cell function; stem cell model; stem cell self renewal; stem cells; stem-like cell; targeted treatment; therapy development; therapy resistant; transcriptome sequencing

Summary/Abstract Leukemia stem cells (LSCs) promote therapeutic resistance and poor clinical outcomes in acute myeloid leukemia (AML). Central to the function of LSCs is a capacity for aberrant self-renewal, but the mechanisms underlying this activity are not well understood. The long-term goal is to identify these mechanisms to develop new therapies that can eradicate LSCs to improve clinical outcomes. The overall objectives in this application are to (i) determine if LSCs from specific genetic subtypes of AML are dependent on regulation of protein synthesis, (ii) determine whether LSCs in high-risk hematopoietic stem cell (HSC)-like AMLs are more dependent on regulated protein synthesis, and (iii) test a novel therapeutic strategy inhibiting protein synthesis in LSCs. The central hypothesis is that LSCs aberrantly self-renew by adopting from normal HSCs a dependence on tightly regulated protein synthesis. The rationale for this project is based on the finding that the cell surface marker CD99 is selectively overexpressed on LSCs and serves to regulate protein synthesis to promote LSC function. This offers a strong scientific framework by which new strategies to deplete LSCs can be developed. The central hypothesis will be tested by pursuing three specific aims: 1) Determining the role of regulated protein synthesis in promoting LSC function; 2) Determining if the cell-of-origin of AML influences the dependence of LSCs on regulated protein synthesis; and 3) Determining if inhibition of protein synthesis can deplete LSCs in high-risk AML. In the first aim, genetically engineered mice will be used to generate models of AML lacking CD99, to test if this leads to dysregulated protein synthesis that impairs LSC self-renewal. LSCs from these models will be evaluated to determine if they require low protein synthesis rates to prevent induction of tumor suppressors, the unfolded protein response, and the integrated stress response. Ribosome profiling will be performed to identify key LSC regulators selectively translated in the context of regulated protein synthesis. In the second aim, we will generate a mouse model of HSC-like AML which mimics high-risk human AML. We will assess if LSCs in HSC- like AML exhibit heightened sensitivity to dysregulated protein synthesis. These studies will be complemented with an evaluation of protein synthesis in HSC-like human LSCs to determine if they also require maintenance of low levels of protein synthesis. The third aim will test if the combination of a ribosome biogenesis-inhibitor with a BCL2-inhibitor currently used to treat AML can eradicate LSCs in high-risk HSC-like AML. The proposal is innovative, in the applicant’s opinion, because it aims to leverage a novel LSC-specific cell surface marker to establish a new paradigm for understanding mechanisms underlying LSC self-renewal. The proposed research is significant because it is expected to provide a strong scientific justification for the development of therapies inhibiting protein synthesis to overcome therapeutic resistance in patients with high-risk AML. Ultimately, the knowledge gained from these studies may offer insights into the mechanisms that promote the function of cancer stem cells in general, opening up opportunities for the development of new strategies to treat cancer.

摘要/摘要 白血病干细胞（LSC）促进急性髓样的热耐药性和临床结果不佳 白血病（AML）。 LSC功能的核心是异常自我更新的能力，但是机制 这项活动的基础尚不清楚。长期目标是确定这些机制以发展 可以放射LSC来改善临床结果的新疗法。此应用程序中的总体目标 要（i）确定来自AML的特定遗传亚型的LSC是否取决于蛋白质的调节 合成，（ii）确定高风险造血干细胞中的LSC（HSC）样AML是否更依赖 关于调节的蛋白质合成，（iii）测试了一种抑制LSC中蛋白质合成的新型热策略。 中心假设是LSC通过从正常的HSC中采用依赖性而异常自我更新 调节的蛋白质合成。该项目的理由是基于细胞表面标记的发现 CD99在LSC上有选择地过表达，并用于调节蛋白质合成以促进LSC功能。 这提供了一个强大的科学框架，可以通过该框架开发新的策略来破坏LSC。中央 假设将通过追求三个特定目的来检验：1）确定调节蛋白质合成的作用 促进LSC功能； 2）确定AML的原始细胞是否影响LSC对LSC的依赖性 调节的蛋白质合成； 3）确定在高风险中是否可以删除蛋白质合成的抑制作用 AML。在第一个目标中，一般设计的小鼠将用于生成缺乏CD99的AML模型，以测试 如果这导致失调的蛋白质合成，从而损害LSC自我更新。这些模型的LSC将是 评估以确定它们是否需要低蛋白质合成速率以防止诱导肿瘤补充剂， 展开的蛋白质反应和综合应力反应。将进行核糖体分析以识别 关键LSC调节剂在调节蛋白质合成的背景下选择性翻译。在第二个目标中，我们将 生成类似于HSC的AML的小鼠模型，该模型模仿了高危人类AML。我们将评估HSC中的LSC是否是 像AML暴露于对蛋白质合成失调的敏感性增强。这些研究将完成 评估HSC样人LSC中蛋白质合成的评估，以确定它们是否还需要维护 低水平的蛋白质合成。第三个目标将测试核糖体生物发生抑制剂与 当前用于治疗AML的BCL2抑制剂可以在高风险HSC样AML中放射性LSC。该提议是 申请人认为，创新性，因为它旨在利用新颖的LSC特异性细胞表面标记 建立一个新的范式来理解LSC自我更新的基础机制。拟议的研究 之所以重要，是因为它有望为疗法的发展提供强有力的科学理由 抑制蛋白质合成以克服高危AML患者的治疗性耐药性。最终， 从这些研究中获得的知识可能会提供有关促进癌症功能的机制的见解 干细胞一般，为制定治疗癌症的新策略开辟了机会。