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

基本信息

批准号：
10400021
负责人：
DONG-ER ZHANG
金额：
$ 62.03万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-16 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10400021
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 Persons 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

项目摘要

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.

概括骨髓增生异常综合征 (MDS) 是一种慢性造血疾病，其特征为发育不良、低效造血功能，以及转化为急性髓系白血病 (AML) 的倾向。最近的进展基因组测序揭示了与该疾病相关的大量突变，大致可分为三类：(1) 参与信号传导的基因（即 FLT3、JAK2、KRAS），(2) 发挥功能的基因染色质和前 mRNA 剪接（即 RUNX1、ASXL1、SRSF2、U2AF1）的水平，以及 (3) 基因负责建立/维护基因组甲基化组（即 DNMT3a、TET2、IDH1/2）。鉴于 MDS 是其临床特征具有高度异质性，一个基本问题是个体突变是否会导致疾病通过不同的机制或许多突变是否在某些聚合途径中发挥作用。支持后一种可能性是MDS患者中许多这些因果突变同时发生。作为以疾病为导向（Zhang）和以机制为中心（Fu）的实验室，我们一直在利用我们的优势结合专业知识，在 R01 资助下共同努力解决该领域的一些紧迫问题，重点关注 RUNX1 和 SRSF2。在过去的资助周期（9/2013至今），我们提出了两个概念突破。首先，通过将 MDS 患者的特定突变与剪接反应联系起来，我们发现非由剪接因子突变引起的重叠反应会收敛到细胞的共同途径循环和 DNA 损伤反应。其次，我们意外地发现，除了他们的传统角色外，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，从而导致复制应激和细胞周期检查点激活。这些发现表明 DNA 损伤反应失调作为 MDS 病因学的共同点。重要的是，这种阐明的共同点奠定了关键的基础为我们下一阶段的研究奠定基础，即了解个体突变对尽管 MDS 在调节基因表达方面发挥着不同的作用，但它们之间存在潜在的协同作用。建筑根据我们已发表和未发表的结果，我们建议在接下来的时间内实现以下具体目标阶段：目标1.RUNX1的功能及其与SRSF2协同预防DNA损伤；目标2.突变体 SRSF2和表观遗传调节因子协同驱动异常基因表达；目标 3. 潜力绕过 R 环诱导的细胞周期检查点激活的机制。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Distinct splicing signatures affect converged pathways in myelodysplastic syndrome patients carrying mutations in different splicing regulators.

不同的剪接特征会影响携带不同剪接调节因子突变的骨髓增生异常综合征患者的聚合通路。

DOI：
发表时间：
2016-10
期刊：
影响因子：
0
作者：
Qiu, Jinsong;Zhou, Bing;Thol, Felicitas;Zhou, Yu;Chen, Liang;Shao, Changwei;DeBoever, Christopher;Hou, Jiayi;Li, Hairi;Chaturvedi, Anuhar;Ganser, Arnold;Bejar, Rafael;Zhang, Dong;Fu, Xiang;Heuser, Michael
通讯作者：
Heuser, Michael

RUNX1 deficiency cooperates with SRSF2 mutation to induce multilineage hematopoietic defects characteristic of MDS.

RUNX1 缺陷与 SRSF2 突变协同诱导 MDS 特征的多系造血缺陷。

DOI：
发表时间：
2022-12-13
期刊：
影响因子：
7.5
作者：
Huang, Yi;Chen, Jia;Yan, Ming;Davis, Amanda G;Miyauchi, Sayuri;Chen, Liang;Hao, Yajing;Katz, Sigrid;Bejar, Rafael;Abdel;Fu, Xiang;Zhang, Dong
通讯作者：
Zhang, Dong