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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.

总结

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.

DOI：
10.1261/rna.056101.116
发表时间：
2016-10
期刊：
RNA (New York, N.Y.)
影响因子：
0
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