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: 10283804
• 负责人: Michael O Alberti
• 金额: $ 16.28万
• 依托单位: WASHINGTON UNIVERSITY
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283804
• 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; Clinical; Clonal Hematopoietic Stem Cell; Codon Nucleotides; Core Facility; DNA Sequence Alteration; Data; Development; Disease; Dysmyelopoietic Syndromes; Elderly; Environment; Felis catus; Functional disorder; Gene Expression; Gene Expression Profile; Gene Mutation; Genes; Genetic; Goals; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Histones; In Vitro; Incidence; Individual; Ineffective Hematopoiesis; Knock-in Mouse; Laboratories; Mediating; Mentors; Modeling; Molecular; Mus; Mutant Strains Mice; Mutate; Mutation; Outcome; Pancytopenia; Pathogenesis; Pathologist; Pathway interactions; Patients; Pattern; Pharmacology; Phenotype; Physicians; Population; Pre-Clinical Model; Protein Isoforms; Proteins; RNA Splicing; Recurrence; Regulation; Research; Research Personnel; Resources; Risk; Role; SRSF2 gene; Salvelinus; Sampling; Scientist; Signal Pathway; Signal Transduction; Spliced Genes; Spliceosomes; Study models; Sum; Testing; Therapeutic; Training; Universities; Washington; Zinc Fingers; base; career; clinical candidate; cytopenia; experimental study; genetic signature; histone modification; in vivo; in vivo Model; molecular pathology; mouse model; mutant; novel; novel therapeutics; programs; self-renewal; success; supportive environment; 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.

项目摘要/摘要 该提案概述了一项为期5年的培训计划，用于将候选人过渡到独立研究者。 候选人的长期目标是成为一个学术医学中心的医师科学家， 除指导外，还 分子病理实验室。提出的培训计划将扩大候选人的临床和 科学背景，并为他提供了支持环境的机会，这将使他为职业做好准备 独立研究者。申请人将由MDS遗传学专家Matthew Walter博士指导 华盛顿大学（WU）的Edward P. Evans MDS中心的生物学和主任。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提供了很好的配备，Wu提供了 丰富的培训和开发环境，作为核心设施，科学资源和临床的访问 样本是例外。本应用程序中概述的实验旨在阐明不同的角色 MDS发病机理中的U2AF1突变体是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，失调的RNA剪接和同时发生有关 MDS患者的基因突变。例如，在ASXL1 cooccur中更频繁地截断突变 MDS患者中的U2AF1Q157比U2AF1S34突变。候选人已经观察到U2AF1S34F/+，并且 U2AF1Q157R/+条件敲门小鼠会形成不同的造血表型，包括细胞质和 具有不同的基因表达模式和造血茎和祖细胞中异常的RNA剪接 （HSPC）。该建议旨在了解U2AF1S34F和 U2AF1Q157R突变体有助于通过MDS患者观察到的造血表型。 确定：（1）MYC和MTORC1途径的激活如何导致HSPC功能障碍和MultiLineAge U2AF1S34F/+小鼠中的细胞质减少以及U2AF1S34F特异性剪接改变是否导致这些激活 途径和（2）突变体ASXL1和U2AF1Q157如何相关的组蛋白修饰和RNA剪接 在MDS发病机理中有选择性合作。解密MYC和MTORC1激活的作用 将允许这些模型用于测试特异性治疗策略以改变细胞质，并且 体内ASXL1和U2AF1突变之间合作的鉴定可能揭示了通过 RNA剪接和组蛋白修饰在MDS中协同作用。总而言之，拟议的研究和培训 环境将促进候选人成为独立调查员的成功。