Delaying age-dependent proteostasis dysfunction in hematopoietic stem cells to restrict the emergence of clonal hematopoiesis and leukemia initiation.

延缓造血干细胞中年龄依赖性蛋白质稳态功能障碍，以限制克隆造血的出现和白血病的发生。

• 批准号: 10831320
• 负责人: Jeffrey Alan Magee
• 金额: $ 15.8万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10831320
• 关键词: 3 year old; Acute Myelocytic Leukemia; Adult; Affect; Age; Aging; Alanine-tRNA Ligase; Anemia; Animals; Award; Biogenesis; Blood; Bone Marrow; Cell Aging; Cell Maintenance; Cells; Cellular Stress; Clonal Hematopoietic Stem Cell; Collaborations; DNA Sequence Alteration; DNMT3a; DNMT3a mutation; Data; Defect; Development; Disease; Elderly; Epigenetic Process; Functional disorder; Funding; Gene Expression; Genes; Genetic; Genetic Models; Goals; Heat shock proteins; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Immune; Immunity; Impairment; Incidence; Investigation; Lead; Life; Link; Longevity; Malignant - descriptor; Malignant Neoplasms; Mus; Mutate; Mutation; Natural regeneration; Organism; Outcomes Research; Parents; Pathway interactions; Predisposition; Protein Biosynthesis; Proteins; Research; Ribosomes; Risk Factors; Testing; Time; Transfer RNA; Translations; Transplantation; age related; aged; biological adaptation to stress; cancer initiation; exhaustion; experience; experimental study; gain of function; hematopoietic stem cell aging; hematopoietic stem cell self-renewal; improved; in vivo; interest; leukemia; misfolded protein; mitochondrial dysfunction; mouse model; mutant; novel; novel strategies; novel therapeutics; postmitotic; preservation; pressure; prevent; progenitor; proteostasis; response; restraint; single-cell RNA sequencing; stem cell function; stem cells

ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 23-045. The goal of the parent 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. 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. A low protein synthesis rate helps maintain proteostasis by preventing the biogenesis of misfolded proteins, and it is required to maintain adult HSC self-renewal capacity. However, we 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. 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. In the parent award (U01CA267031), we set out to determine if proteostasis disruption promotes clonal hematopoiesis and AML initiation during aging. Now, in collaboration with Dr. Eric Bennett, we generated a new genetic mouse model (Rps23K60R) with a mutation in the decoding region of the ribosome that enhances translation fidelity and mitigates proteostasis disruption in aging HSCs. These animals are viable, grossly normal, fertile and can live beyond 3 years of age and have functional HSCs as determined in transplantation studies. Using this new mouse model, our goal is to extend our parental award to directly test if preserving proteostasis in HSCs restricts the emergence of clonal hematopoiesis and impedes AML initiation. We will test whether delaying proteostasis disruption prevents clonal hematopoiesis and AML initiation during aging in the setting of a Dnmt3aR878H mutation. We will also examine if enhanced translation fidelity in Rps23K60R animals impedes AML initiation in aging HSCs using Dnmt3aR878H mutant animals with a cooperating NrasG12D mutation. Research outcomes from this supplemental research will determine if enhancing translation fidelity restrains the emergence of clonal hematopoiesis and reduces the incidence of AML in older animals. These studies will open new lines of investigation into a previously unappreciated link between age- related proteostasis alterations and leukemia initiation. Therapies that sustain proteostasis may not only preserve HSC function during later stages of life, but also may prevent AML initiation.

摘要 本申请是为了响应被标识为NOT-CA的特别利益通知（NOSI）而提交的- 23-045.父母提案的目标是了解衰老过程中蛋白质稳态的丧失 造血干细胞（HSC）的选择性压力促进白血病的发生。 蛋白质稳态的丧失是衰老的最不为人所知的标志之一，特别是当它与恶性肿瘤相关时。 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HSC对蛋白质稳态的丧失特别敏感。成年HSC的 相对于更频繁分裂的谱系定型血祖细胞的蛋白质合成。低蛋白 合成速率有助于通过防止错误折叠蛋白质的生物发生来维持蛋白质稳态，并且这是必需的。 维持成年HSC的自我更新能力。然而，我们发现，老化的HSC经历了显著的 体内蛋白质应激，蛋白质稳态必须通过基因表达的变化来积极维持， 维持HSC自我更新活性和寿命的应激反应途径。这些数据表明， HSC必须积极维持蛋白质稳态以保持功能，蛋白质稳态的丧失可能会产生选择性的细胞凋亡。 促进克隆造血和白血病发生的压力。根据这些数据，我们假设， 衰老HSC中蛋白质稳态和维持蛋白质稳态的压力的丧失促进克隆造血， 急性髓细胞白血病（AML）在老年人开始。在母公司裁决（U 01 CA 267031）中，我们着手 确定蛋白质稳态破坏是否促进衰老过程中的克隆造血和AML启动。现在 与Eric班尼特博士合作，我们产生了一种新的遗传小鼠模型（Rps 23 K60 R），其基因突变发生在 核糖体的解码区域，增强翻译保真度并减轻衰老中蛋白质稳态的破坏 HSC。这些动物是可行的，大体上正常的，可生育的，可以活超过3岁，并具有功能性 在移植研究中确定的HSC。使用这种新的小鼠模型，我们的目标是扩大我们的父母， 该奖项旨在直接测试HSC中蛋白质稳态的保留是否限制了克隆造血的出现， 阻碍AML启动。我们将测试延迟蛋白质稳态破坏是否会阻止克隆性造血， 在Dnmt 3aR 878 H突变的背景下，在衰老期间AML的发生。我们还将研究是否增强翻译 Rps 23 K60 R动物的保真度阻碍了使用具有Dnmt 3aR 878 H突变体动物的老化HSC中的AML起始， 协同NrasG 12 D突变。这项补充研究的研究结果将决定是否加强 翻译保真度抑制了克隆性造血的出现，并降低了老年人AML的发病率。 动物这些研究将开辟新的调查路线，以了解以前未被重视的年龄之间的联系- 相关的蛋白质稳态改变和白血病的发生。维持蛋白质稳态的疗法不仅可以保护 HSC在生命的后期发挥作用，但也可以预防AML的发生。