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: 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
• 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

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 骨髓增生综合征（MDS）是慢性造血疾病，其特征是发育不良，效率低下 造血，以及转化为急性髓样白血病（AML）的倾向。最近的进步 基因组测序显示与该疾病相关的大量突变可以大致 分为三类：（1）与信号传导有关的基因（即FLT3，JAK2，KRAS），（2） 染色质和前MRNA剪接的水平（即Runx1，asxl1，Srsf2，U2AF1）和（3）基因 负责建立/维持基因组甲基体（即DNMT3A，TET2，IDH1/2）。给定MD是 高度异质的临床特征，一个基本问题是个体突变是否导致 通过不同的机制疾病，或者许多突变在某些融合途径中是否起作用。支持 后一种可能性是MDS患者中许多这些因果突变的共发生。 作为面向疾病的（Zhang）和机理中心（FU）实验室，我们一直在利用自己的优势 将专业知识合并为在此资助的R01下共同努力，以攻击该领域的一些紧迫问题， 专注于runx1和srsf2。在过去的融资周期（9/2013至今）中，我们进行了两个概念 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 - 剪接因子突变引起的重叠响应被收敛于细胞的共同途径 循环和DNA损伤响应。其次，我们出乎意料地发现了这一点，除了它们的传统角色 剪接，关键剪接因子中的所有因果突变触发过多的R环形成，导致复制 压力和细胞周期检查点激活。这些发现指出DNA损伤响应失调 作为MDS病因的共同基础。重要的是，这种阐明的共同基础已经为 我们下一阶段调查的基础，即了解个体突变对 尽管MDS及其潜在的协同作用在调节基因表达方面具有多种作用。建筑 在我们已发表和未发表的结果之间，我们建议在下一个中追求以下具体目标 阶段：AIM 1。runx1的功能及其与SRSF2的协同作用在防止DNA损伤方面；目标2。突变体 SRSF2和表观遗传调节剂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

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

• DOI: 10.1261/rna.056101.116
• 发表时间: 2016-10
• 期刊: RNA (New York, N.Y.)
• 作者: Qiu J;Zhou B;Thol F;Zhou Y;Chen L;Shao C;DeBoever C;Hou J;Li H;Chaturvedi A;Ganser A;Bejar R;Zhang DE;Fu XD;Heuser M
• 通讯作者: Heuser M

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

• DOI: 10.1182/bloodadvances.2022007804
• 发表时间: 2022-12-13
• 期刊: BLOOD ADVANCES
• 影响因子: 7.5
• 作者: Huang, Yi-Jou;Chen, Jia-Yu;Yan, Ming;Davis, Amanda G.;Miyauchi, Sayuri;Chen, Liang;Hao, Yajing;Katz, Sigrid;Bejar, Rafael;Abdel-Wahab, Omar;Fu, Xiang-Dong;Zhang, Dong-Er
• 通讯作者: Zhang, Dong-Er