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.

总结/摘要 白血病干细胞（LSC）促进急性髓系白血病患者的治疗耐药性和不良临床结局 白血病（AML）。LSC功能的核心是异常自我更新的能力，但其机制 这一活动背后的原因并不十分清楚。长期目标是确定这些机制， 新的疗法可以根除LSC，以改善临床结果。本申请的总体目标是 （i）确定来自AML的特定遗传亚型的LSC是否依赖于蛋白质表达的调节， （ii）确定高危造血干细胞（HSC）样AML中的LSC是否更依赖于 调节蛋白质合成，和（iii）测试抑制LSC中蛋白质合成的新治疗策略。的 中心假设是LSC通过从正常HSC中吸收紧密依赖于 调节蛋白质合成。该项目的基本原理是基于细胞表面标记物的发现 CD 99在LSC上选择性过表达，并用于调节蛋白质合成以促进LSC功能。 这提供了一个强有力的科学框架，可以据此制定消耗LSC的新战略。中央 我们将通过以下三个具体目标来检验这一假设：1）确定受调控的蛋白质合成的作用 2）确定AML的起源细胞是否影响LSC对以下的依赖性： 调节蛋白质合成;和3）确定蛋白质合成的抑制是否可以消耗高风险中的LSC。 急性髓细胞白血病在第一个目标中，基因工程小鼠将用于产生缺乏CD 99的AML模型，以测试 如果这导致蛋白质合成失调，损害LSC的自我更新。这些模型的LSC将 评估以确定它们是否需要低蛋白质合成速率来防止肿瘤抑制剂的诱导， 未折叠蛋白反应和整合应激反应。将进行核糖体分析，以确定 关键LSC调节剂在调节蛋白质合成的背景下选择性翻译。第二个目标，我们将 产生模拟高风险人类AML的HSC样AML的小鼠模型。我们将评估HSC中的LSC是否- 如AML表现出对失调的蛋白质合成的高度敏感性。这些研究将得到补充 评估HSC样人LSC中的蛋白质合成，以确定它们是否也需要维持 低水平的蛋白质合成。第三个目标将测试核糖体生物合成抑制剂与 目前用于治疗AML的BCL 2抑制剂可以根除高危HSC样AML中的LSC。该提案 在申请人看来，这是创新的，因为它旨在利用新的LSC特异性细胞表面标志物， 为理解LSC自我更新的机制建立一个新的范式。拟议研究 是重要的，因为它有望为治疗的发展提供强有力的科学依据。 抑制蛋白质合成，以克服高危AML患者的治疗耐药性。最终 从这些研究中获得的知识可能有助于了解促进癌症功能的机制。 干细胞，为开发治疗癌症的新策略提供了机会。