Distinct roles of U2AF1 mutations in myelodysplastic syndrome pathogenesis

U2AF1突变在骨髓增生异常综合征发病机制中的独特作用

• 批准号: 10687028
• 负责人: Michael O Alberti
• 金额: $ 16.28万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-09 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687028
• 关键词: 3' Splice Site; Academic Medical Centers; Acute Myelocytic Leukemia; Advisory Committees; Alternative Splicing; Animal Model; Automobile Driving; Basic Science; Biological Models; Biology; Blood; Bone Marrow Cells; Bone marrow failure; Clinical; Clonal Hematopoietic Stem Cell; Codon Nucleotides; Core Facility; DNA Sequence Alteration; Data; Development; Disease; Dysmyelopoietic Syndromes; Elderly; Environment; Functional disorder; Gene Expression; Gene Expression Profile; Gene Mutation; Genes; Genetic; Goals; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Heterozygote; Histones; In Vitro; Incidence; Individual; Ineffective Hematopoiesis; Knock-in Mouse; Laboratories; Mediating; Mentors; Modeling; Molecular; Mus; Mutant Strains Mice; Mutate; Mutation; Outcome; Pathogenesis; Pathologist; Pathway interactions; Patients; Pattern; Phenotype; Physicians; Population; Pre-Clinical Model; Protein Isoforms; Proteins; RNA Splicing; Recurrence; Regulation; Research; Research Personnel; Resources; Role; SRSF2 gene; Sampling; Scientist; Signal Pathway; Signal Transduction; Spliced Genes; Spliceosomes; Study models; Testing; Therapeutic; Training; Universities; Washington; Zinc Fingers; career; clinical candidate; cytopenia; experimental study; genetic signature; histone modification; in vivo; in vivo Model; molecular pathology; mouse model; mutant; novel; novel therapeutics; pharmacologic; programs; progression risk; self-renewal; success; supportive environment; synergism; therapeutic evaluation; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT This proposal outlines a 5-year training plan for the transition of the candidate to an independent investigator. The long-term goal of the candidate is to be a physician-scientist at an academic medical center studying the molecular basis of genetic mutations in myelodysplastic syndrome (MDS) pathogenesis, in addition to directing a molecular pathology laboratory. The training plan proposed will expand upon the candidate's clinical and scientific background and provide him access to a supportive environment that will prepare him for a career as an independent investigator. The applicant will be mentored by Dr. Matthew Walter, an expert in MDS genetics and biology and Director of the Edward P. Evans Center for MDS at Washington University (WU). An advisory committee consisting of basic science and clinical/translational MDS experts and pathologists will provide scientific and career advice. The applicant's laboratory is well equipped for these studies, and WU provides a rich environment for training and development as access to core facilities, scientific resources, and clinical samples is exceptional. The experiments outlined in this application aim to clarify the distinct roles of different U2AF1 mutants in MDS pathogenesis, as highly recurrent heterozygous mutations in splicing factor genes (e.g., U2AF1) occur in over half of MDS patients. Hotspot mutations in U2AF1 (encoding U2AF1S34 and U2AF1Q157 mutants) are associated with different clinical features, outcomes, dysregulated RNA splicing, and co-occurring gene mutations in patients with MDS. For example, truncating mutations in ASXL1 cooccur more frequently with U2AF1Q157 than with U2AF1S34 mutations in MDS patients. The candidate has observed U2af1S34F/+ and U2af1Q157R/+ conditional knock-in mice develop different hematopoietic phenotypes, including cytopenias, and have distinct gene expression patterns and aberrant RNA splicing in hematopoietic stem and progenitor cells (HSPC). This proposal aims to understand how the distinct molecular perturbations induced by U2AF1S34F and U2AF1Q157R mutants contribute to the divergent hematopoietic phenotypes observed in MDS patients by determining: (1) how activation of MYC and mTORC1 pathways leads to HSPC dysfunction and multilineage cytopenias in U2af1S34F/+ mice and whether U2AF1S34F-specific splicing alterations result in activation of these pathways, and (2) how mutant ASXL1 and U2AF1Q157 associated histone modification and RNA splicing aberrancies selectively cooperate in MDS pathogenesis. Deciphering the role of MYC and mTORC1 activation will allow these models to be used to test pathway-specific therapeutic strategies to alter cytopenias, and identification of cooperation between ASXL1 and U2AF1 mutations in vivo may reveal novel mechanisms by which RNA splicing and histone modifications synergize in MDS. In sum, the proposed studies and training environment will facilitate the candidate's success in becoming an independent investigator.

项目概要/摘要 该提案概述了候选人向独立调查员过渡的 5 年培训计划。 候选人的长期目标是成为学术医学中心的医师科学家，研究 骨髓增生异常综合征（MDS）发病机制中基因突变的分子基础，除了指导 分子病理学实验室。拟议的培训计划将扩展候选人的临床和 科学背景并为他提供支持性环境，为他的职业生涯做好准备 独立调查员。申请人将得到MDS遗传学专家Matthew Walter博士的指导 华盛顿大学 (WU) 爱德华·P·埃文斯 MDS 中心主任、生物学家。咨询 由基础科学和临床/转化 MDS 专家和病理学家组成的委员会将提供 科学和职业建议。申请人的实验室为这些研究配备了良好的设备，并且WU提供了 丰富的培训和发展环境，包括使用核心设施、科学资源和临床 样品非常出色。本申请中概述的实验旨在阐明不同的角色的不同作用 MDS 发病机制中的 U2AF1 突变体，作为剪接因子基因中高度复发的杂合突变（例如， U2AF1) 发生在超过一半的 MDS 患者中。 U2AF1 中的热点突变（编码 U2AF1S34 和 U2AF1Q157 突变体）与不同的临床特征、结果、RNA剪接失调以及同时发生相关 MDS 患者的基因突变。例如，ASXL1 的截短突变与 U2AF1Q157 突变的 MDS 患者优于 U2AF1S34 突变的 MDS 患者。候选人观察到 U2af1S34F/+ 和 U2af1Q157R/+条件敲入小鼠产生不同的造血表型，包括血细胞减少症和 造血干细胞和祖细胞中具有独特的基因表达模式和异常的 RNA 剪接 （HSPC）。该提案旨在了解 U2AF1S34F 和 U2AF1S34F 引起的不同分子扰动如何 U2AF1Q157R 突变体导致 MDS 患者中观察到的不同造血表型 确定：(1) MYC 和 mTORC1 通路的激活如何导致 HSPC 功能障碍和多谱系 U2af1S34F/+ 小鼠中的血细胞减少症以及 U2AF1S34F 特异性剪接改变是否会导致这些细胞的激活 途径，以及 (2) 突变体 ASXL1 和 U2AF1Q157 如何关联组蛋白修饰和 RNA 剪接 异常选择性地参与 MDS 发病机制。解读 MYC 和 mTORC1 激活的作用 将允许使用这些模型来测试改变血细胞减少症的途径特异性治疗策略，并且 体内 ASXL1 和 U2AF1 突变之间合作的鉴定可能揭示新的机制： RNA 剪接和组蛋白修饰在 MDS 中协同作用。总之，拟议的研究和培训 环境将有助于候选人成功成为一名独立调查员。