Biologic and Therapeutic Consequences of Distinct Hotspot SF3B1 Mutations in MDS

MDS 中不同热点 SF3B1 突变的生物学和治疗后果

• 批准号: 10653193
• 负责人: AMY E DEZERN
• 金额: $ 40.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653193
• 关键词: Affect; Amino Acids; Anemia; Biological; Biology; Blood Cells; Bone Marrow; Bone marrow failure; Cell model; Cells; Cellular biology; Clinical; Clinical Data; Clinical Investigator; Clinical Research; Collection; Computer Analysis; Credentialing; Data; Differentiation and Growth; Disease; Disease Management; Disease model; Dysmyelopoietic Syndromes; Erythroid; Event; Genes; Genetic; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Cell Production; Hemorrhage; Heterogeneity; Human; Impairment; In Vitro; Individual; Indolent; Infection; Institution; Introns; Knowledge; Learning; Maps; Marrow; Mediating; Metabolic; Metabolism; Molecular Abnormality; Multiple Organ Failure; Multivariate Analysis; Mus; Mutate; Mutation; Myelogenous; National Heart, Lung, and Blood Institute; Outcome; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Physicians; Privatization; Process; Production; Prognosis; Prognostic Marker; Progressive Disease; Publications; Publishing; RNA; RNA Splicing; Resources; Risk; Role; Sampling; Scientist; Serine; Sideroblast; Sideroblastic Anemia; Spliced Genes; Spliceosomes; Testing; Therapeutic; Work; clinical phenotype; cytopenia; dalton; disease classification; disease phenotype; disease prognosis; fitness; human model; improved; in vivo; insight; mutant; novel; novel therapeutic intervention; response; response biomarker; stem cells; transcriptome sequencing; treatment response

Project Summary The myelodysplastic syndromes (MDS) are the most common clonal blood disorders, characterized by dominance of the bone marrow by abnormal stem cells and impairment of blood cell production. Patients with MDS suffer from combinations of anemia, infection, bleeding, and multiorgan failure from progressive disease. Outcomes are poor, and treatments are inadequate. Key to developing new treatments is better understanding of the mutations which create these diseases. Roughly half of MDS patients have mutations in spliceosome genes, and of these, SF3B1 is the most commonly mutated. Mutant SF3B1 is neomorphic, disrupting RNA splicing to create what we refer to as JEMs (splice Junctions Enriched in Mutant-spliceosome cells), though how JEMs produce MDS phenotypes is unknown. SF3B1 mutation is regarded as a favorable prognostic marker in MDS. Yet, there is considerable heterogeneity in the pathologic features and clinical outcomes of SF3B1-mutant MDS that remains unexplained. As this heterogeneity beguiles effective disease management, its causes need to be better understood. The premise of our proposal is that a key to understanding SF3B1-mutant MDS is to study the differences between distinct SF3B1 mutations. This gene is mutated in hotspots affecting multiple amino acids, and our preliminary data show that specific mutations associate with distinct clinical features, RNA splicing patterns, and responses to therapy. We also have data that SF3B1 mutations disrupt metabolism in specific ways that likely affect sideroblastic anemia and metabolic vulnerabilities, and we have developed novel human models of SF3B1-mutant hematopoiesis with which to study these processes. The proposed work combines the expertise of a physician-scientist (Dr. Dalton) who specializes in cell biology, genetics, and human cell modeling of disease with that of a clinical investigator (Dr. DeZern) who specializes in clinical studies of bone marrow failure disorders. Together, we will pursue three aims: 1) Characterize the landscape of private and shared JEMs among hotspot SF3B1 mutations in MDS. We will use RNA-seq of primary MDS samples and isogenic human cell models to map the RNA splicing landscape of different SF3B1 mutations and use this as a ‘way in’ to understanding the pathways they disrupt. 2) Establish the role of distinct SF3B1 mutations in the growth and differentiation of human hematopoietic cells. We will use primary MDS samples and isogenic cells to determine mechanisms of sideroblastic anemia, cell fitness, and metabolic vulnerability in SF3B1-mutant hematopoietic cells. 3) Define the clinicopathologic features of distinct SF3B1 mutations in MDS. Leveraging the high-quality data from the NHLBI National MDS Study, we will determine how distinct hotspot SF3B1 mutations affect pathologic and clinical features of MDS through multivariate analysis. Successful completion of these aims promises to reveal pathophysiologic mechanisms of RNA splicing, redefine disease classification and prognosis, and improve treatment approaches in MDS.

项目概要 骨髓增生异常综合征 (MDS) 是最常见的克隆性血液疾病，其特征是 异常干细胞对骨髓的支配和血细胞生成受损的患者。 MDS 患有贫血、感染、出血和进行性疾病导致的多器官衰竭。 结果很差，治疗方法也不充分 开发新疗法的关键是更好地了解。 造成这些疾病的突变中，大约一半的 MDS 患者存在剪接体突变。 其中，SF3B1 是最常见的突变体，SF3B1 是新形态的，会破坏 RNA。 剪接以创建我们所说的 JEM（富含突变剪接体细胞的剪接连接点），但如何 JEM 产生的 MDS 表型尚不清楚，SF3B1 突变被认为是一种有利的预后标志物。 然而，SF3B1 突变体的病理特征和临床结果存在相当大的异质性。 MDS 仍无法解释 由于这种异质性影响了有效的疾病管理，因此需要对其原因进行研究。 为了更好地理解，我们建议的前提是理解 SF3B1 突变体 MDS 的关键是 研究不同 SF3B1 突变之间的差异 该基因在影响多个的热点中发生突变。 氨基酸，我们的初步数据表明特定突变与不同的临床特征、RNA 我们还有数据表明 SF3B1 突变会扰乱新陈代谢。 可能影响铁粒幼细胞贫血和代谢脆弱性的具体方法，我们已经开发出新的 SF3B1 突变造血的人类模型，用于研究这些过程。 结合了专门研究细胞生物学、遗传学和人类学的医师科学家（道尔顿博士）的专业知识 与专门从事骨临床研究的临床研究人员（DeZern 博士）一起建立疾病细胞模型 我们将共同追求三个目标：1）描述私人和骨髓衰竭疾病的特征。 MDS 中的热点 SF3B1 突变之间共享 JEM 我们将使用原始 MDS 样本的 RNA-seq 和 同基因人类细胞模型绘制不同 SF3B1 突变的 RNA 剪接图谱，并将其用作 “方式”来了解它们破坏的途径 2) 确定不同 SF3B1 突变在 我们将使用原代MDS样本和同基因细胞来进行人类造血细胞的生长和分化。 确定 SF3B1 突变体铁粒幼细胞贫血、细胞适应性和代谢脆弱性的机制 3) 利用 MDS 定义不同 SF3B1 突变的临床病理特征。 来自 NHLBI 国家 MDS 研究的高质量数据，我们将确定 SF3B1 热点突变的不同程度 通过多变量分析影响MDS的病理和临床特征成功完成这些目标。 有望揭示RNA剪接的病理生理机制，重新定义疾病分类和预后， 并改进 MDS 的治疗方法。