The influence of proteostasis loss in aging hematopoietic stem cells on leukemia initiation

衰老造血干细胞蛋白稳态丧失对白血病发生的影响

• 批准号: 10700998
• 负责人: Jeffrey Alan Magee
• 金额: $ 35.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700998
• 关键词: Acceleration; Acute; Acute Myelocytic Leukemia; Adult; Affect; Age; Aging; Alanine-tRNA Ligase; Attenuated; Biogenesis; Biological; Biological Assay; Blood; Cell Aging; Cells; Cellular Stress; Chronic; Clonal Hematopoietic Stem Cell; DNA Sequence Alteration; DNMT3a; DNMT3a mutation; Data; Defect; Development; Disease; Elderly; Environment; Epigenetic Process; Equilibrium; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Heat shock proteins; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Incidence; Investigation; Life; Link; Longevity; Malignant - descriptor; Malignant Neoplasms; Modeling; Mus; Mutate; Mutation; Organism; Pathway interactions; Predisposition; Protein Biosynthesis; Proteins; Proteome; Risk Factors; Stress; Testing; Time; Transfer RNA; Translations; age related; aged; biological adaptation to stress; cancer initiation; exhaustion; experience; experimental study; hematopoietic stem cell aging; hematopoietic stem cell emergence; hematopoietic stem cell self-renewal; improved; in vivo; leukemia; misfolded protein; mitochondrial dysfunction; mutant; novel strategies; novel therapeutics; permissiveness; postmitotic; preservation; pressure; prevent; progenitor; programs; proteostasis; response; sensor; single-cell RNA sequencing; stem cells; young adult

ABSTRACT The goal of this proposal is to understand how loss of protein homeostats (proteostasis) in aging blood-forming hematopoietic stem cells (HSCs) applies a selective pressure that promotes leukemia initiation. Loss of proteostasis is one of the least understood hallmarks of aging, particularly as it relates to malignant transformation. As an organism ages, misfolded proteins can accumulate in post-mitotic cells, or in cells that are largely quiescent. This stresses the cell and can drive adaptive changes that are required to rebalance proteostasis. HSCs are particularly susceptible to a loss of proteostasis. Adult HSCs have low rates of protein synthesis relative to more frequently dividing lineage-committed blood progenitors. This helps maintain proteostasis by preventing the biogenesis of misfolded proteins, and it is required to maintain adult HSC self- renewal capacity. However, we have discovered that aged HSCs experience significant protein stress in vivo, and proteostasis must be actively maintained through changes in gene expression and stress-response pathways to sustain HSC self-renewal activity and longevity. In this regard, we have generated preliminary data demonstrating that Hsf1, a critical proteostasis sensor that dynamically remodels the proteostasis network in response to stress, is activated within aging HSCs where it is required to attenuate protein synthesis and preserve HSC self-renewal capacity. These data indicate that aged HSCs must actively maintain proteostasis to remain functional, and loss of proteostasis may create a selective pressure that promotes clonal hematopoiesis and leukemia initiation. Based on these data, we hypothesize that a loss of proteostasis and pressure to maintain proteostasis in aging HSCs promotes clonal hematopoiesis and acute myeloid leukemia (AML) initiation in older adults. We propose two aims to test this hypothesis. In the first aim, we will use Aarssti/sti mice, which have a defect in tRNA editing activity, to disrupt proteostasis in young and old adult mice. We will test whether proteostasis disruption accelerates clonal hematopoiesis and AML initiation during aging in the setting of Dnmt3aR878H and Tet2D/D mutations. In the second aim, we will test if normal age-related activation of Hsf1 creates a permissive context for AML initiation in aging HSCs. We will conditionally delete Hsf1 in young and old adult HSCs in the setting of a Dnmt3aR878H mutation with and without a cooperating NrasG12D mutation to determine if it contributes to the emergence of clonal hematopoiesis and increased incidence of AML in older adults. These studies will open new lines of investigation into a previously unappreciated link between age-related loss of proteostasis (a hallmark of aging) and leukemia initiation. Therapies that mitigate proteostasis dysfunction could preserve HSC clonal diversity later in life while reducing susceptibility to AML.

摘要 这项建议的目的是了解衰老血液形成过程中蛋白质稳态（蛋白质稳态）的丧失是如何发生的。 造血干细胞（HSC）施加促进白血病起始的选择性压力。损失 蛋白质稳态是最不了解的衰老标志之一，特别是当它涉及恶性肿瘤时。 转型随着生物体的衰老，错误折叠的蛋白质可以在有丝分裂后的细胞中积累，或者在有丝分裂后的细胞中积累。 大部分是静止的这会给细胞带来压力，并可以驱动重新平衡所需的适应性变化 蛋白质稳态HSC对蛋白质稳态的丧失特别敏感。成年HSC的蛋白质表达率低， 相对于更频繁分裂的谱系定向血液祖细胞的合成。这有助于保持 通过阻止错误折叠蛋白质的生物发生来实现蛋白质稳态，并且需要维持成体HSC自身的 更新能力。然而，我们已经发现，老化的HSC在体内经历显著的蛋白质应激， 蛋白质稳态必须通过基因表达和应激反应的变化来积极维持 维持HSC自我更新活性和寿命的途径。在这方面，我们已经生成了初步数据， 证明了Hsf 1，一个关键的蛋白质稳态传感器，动态重塑蛋白质稳态网络， 对应激的反应，在老化的HSC内被激活，其中需要减弱蛋白质合成， 保持HSC自我更新能力。这些数据表明，老化的HSC必须积极维持蛋白质稳态， 保持功能，蛋白质稳态的丧失可能产生促进克隆造血的选择性压力 和白血病的发生基于这些数据，我们假设蛋白质稳态和维持压力的丧失 衰老HSC中的蛋白质稳态促进老年人的克隆性造血和急性髓细胞白血病（AML）的发生。 成年人了我们提出了两个目标来检验这一假设。在第一个目标中，我们将使用Aarssti/sti小鼠，其具有 tRNA编辑活性的缺陷，破坏年轻和老年成年小鼠的蛋白质稳态。我们将测试 蛋白质稳态破坏加速克隆造血和AML启动在衰老的背景下， Dnmt 3aR 878 H和Tet 2D/D突变。在第二个目标中，我们将测试正常的与年龄相关的Hsf 1激活是否会产生 在老化的HSC中AML起始的容许环境。我们将有条件地删除青年和老年人的Hsf 1 在具有和不具有协同NrasG 12 D突变的Dnmt 3aR 878 H突变的情况下的HSC，以确定 它有助于克隆造血的出现和老年人AML发病率的增加。这些 研究将开辟新的调查路线，以了解以前未被重视的与年龄有关的损失之间的联系。 蛋白质稳态（衰老的标志）和白血病的发生。减轻蛋白质稳态功能障碍的疗法可以 在以后的生活中保持HSC克隆多样性，同时降低对AML的易感性。