Synergestic roles of SRF2 and RUNX1 in blood cell development and pathology

SRF2 和 RUNX1 在血细胞发育和病理学中的协同作用

• 批准号: 9922899
• 负责人: DONG-ER ZHANG
• 金额: $ 64.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922899
• 关键词: Acute Myelocytic Leukemia; Affect; Animal Model; Biology; Blood Cells; Bone Marrow Cells; Bypass; Cell Aging; Cell Cycle; Cell Cycle Checkpoint; Cell model; Chromatin; Chronic; Clinical; Complement; DNA Damage; DNMT3a; Defect; Development; Disease; Dysmyelopoietic Syndromes; Dysplasia; Epigenetic Process; Etiology; Event; FLT3 gene; Failure; Foundations; Functional disorder; Funding; Gene Abnormality; Gene Expression; Gene Mutation; Genes; Genetic Transcription; Genome; Genomic approach; Genomics; Hematological Disease; Hematopoiesis; Hematopoietic; Individual; Induced Mutation; Investigation; JAK2 gene; KRAS2 gene; Lead; Link; Maps; Methyltransferase; Molecular; Mutation; Oncogenic; Pathology; Pathway interactions; Patients; Phase; Play; Protein Tyrosine Kinase; Publishing; Quality of life; RNA Splicing; RUNX1 gene; Resolution; Role; SRSF2 gene; SS DNA BP; Signal Transduction; Solid Neoplasm; Syndrome; Technology; Testing; Tumor Biology; Work; base; causal variant; disease phenotype; disease-causing mutation; driver mutation; effective therapy; functional genomics; gain of function; gene function; insight; interest; mRNA Precursor; methylome; mutant; novel; prevent; replication stress; response; synergism; theories

Summary Myelodysplastic Syndromes (MDS) are chronic hematopoietic disorders characterized by dysplasia, inefficient hematopoiesis, and the propensity to transform into acute myeloid leukemia (AML). Recent advances in genomic sequencing revealed a large number of mutations associated with the disease, which can be roughly grouped into three classes: (1) genes involved in signaling (i.e. FLT3, JAK2, KRAS), (2) genes functioning at the levels of chromatin and pre-mRNA splicing (i.e. RUNX1, ASXL1, SRSF2, U2AF1), and (3) genes responsible for establishing/maintaining the genome methylome (i.e. DNMT3a, TET2, IDH1/2). Given MDS is highly heterogeneous in its clinical features, a fundamental question is whether individual mutations cause the disease via distinct mechanisms or whether many mutations function in some converging pathways. Support of the latter possibility is the co-occurrence of many of these causal mutations in MDS patients. As disease-oriented (Zhang) and mechanism-central (Fu) labs, we have been taking advantage of our combined expertise to work together under this funded R01 to attack some pressing questions in the field, focusing on RUNX1 and SRSF2. In the past funding cycle (9/2013-present), we have made two conceptual breakthroughs. First, by linking specific mutations to splicing responses in MDS patients, we found that non- overlapping responses induced by splicing factor mutations are converged to the common pathways of cell cycle and DNA damage response. Second, we unexpectedly uncovered that, besides their traditional roles in splicing, all causal mutations in key splicing factors trigger excessive R-loop formation, leading to replication stress and cell cycle checkpoint activation. These findings point to dysregulation of the DNA damage response as a common ground for MDS etiology. Importantly, such elucidated common ground has laid a critical foundation for our next phase of investigation, which is to understand the contribution of individual mutations to MDS and potential synergy among them, despite their diverse roles in regulating gene expression. Building upon both our published and unpublished results, we propose to pursue the following specific aims in the next phase: Aim 1. Function of RUNX1 and its synergy with SRSF2 in preventing DNA damage; Aim 2. Mutant SRSF2 and epigenetic regulators to synergistically drive aberrant gene expression; Aim 3. Potential mechanism for bypassing R-loop-induced cell cycle checkpoint activation.

总结 骨髓增生异常综合征（MDS）是一种慢性造血系统疾病，其特征是发育异常，低效， 白血病是一种急性白血病，它具有造血功能和转化为急性髓性白血病（AML）的倾向。的最新进展 基因组测序揭示了大量与该疾病相关的突变， 分为三类：（1）参与信号传导的基因（即FLT 3、JAK 2、KRAS），（2）在 染色质和前体mRNA剪接（即RUNX 1、ASXL 1、SRSF 2、U2 AF 1）的水平，以及（3）基因 负责建立/维持基因组甲基化组（即DNMT 3a、TET 2、IDH 1/2）。鉴于MDS是 在其临床特征高度异质性，一个基本的问题是，是否个别突变引起的， 疾病通过不同的机制，或是否有许多突变在一些会聚途径中发挥作用。支持 后一种可能性是MDS患者中许多这些致病突变的共同发生。 作为疾病导向（Zhang）和机制中心（Fu）实验室，我们一直在利用我们的 结合专业知识，在此资助的R 01下共同努力，解决该领域的一些紧迫问题， RUNX 1和SRSF 2。在上一个供资周期（2013年9月至今）， 突破首先，通过将特定突变与MDS患者的剪接反应联系起来，我们发现非- 由剪接因子突变诱导的重叠反应会聚到细胞的共同途径， 循环和DNA损伤反应。第二，我们意外地发现，除了他们的传统角色， 剪接时，关键剪接因子中的所有因果突变都会触发过度的R环形成，导致复制 应激和细胞周期检查点激活。这些发现指出了DNA损伤反应的失调 作为MDS病因学的共同基础。重要的是，这种阐明的共同点奠定了关键的 这是我们下一阶段研究的基础，这是为了了解单个突变对 MDS和潜在的协同作用，尽管他们在调节基因表达的不同作用。建筑 根据我们已发表和未发表的研究结果，我们建议在下一阶段实现以下具体目标： 阶段：目标1。RUNX 1的功能及其与SRSF 2在防止DNA损伤中的协同作用;目的2.突变体 SRSF 2和表观遗传调节剂协同驱动异常基因表达;目的3。潜在 绕过R环诱导的细胞周期检查点激活的机制。