Molecular Mechanisms of Impaired DAN Damage Response in Leukemia Pathogenesis

白血病发病机制中 DAN 损伤反应受损的分子机制

基本信息

批准号：
8189005
负责人：
JAMES J HSIEH
金额：
$ 37.57万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-12 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8189005
关键词：
11q23 A Mouse Address Alleles Amino Acids Binding Biological Process Bone Marrow Cells CDC45L gene Cancer Patient Cell Cycle Cell Cycle Checkpoint Cells Chromatids Chromatin Chromosomal translocation Chromosome Band Complex DNA DNA Damage DNA biosynthesis Data Defect Dominant-Negative Mutation Embryo Event Evolution Exhibits Fibroblasts Functional disorder Future Gene Expression Genes Genetic Genetic Models Genetic Transcription Genome Genome Stability Genomic Instability Genomics Genotoxic Stress Grant HRX protein Histone H3 Histones Homeobox Genes Human Hybrids In Vitro Incidence Knock-in Mouse Laboratories Light Link Lysine MLL gene Malignant Neoplasms Mammalian Cell Mediating Mitosis Modeling Molecular Mus Myeloid Progenitor Cells N-terminal Normal Cell Oncogene Deregulation Organism Pathogenesis Phase Transition Phenotype Phosphorylation Physiological Pre-Replication Complex Predisposition Proteins Public Health Regulation Replication Origin S Phase Serine Signal Transduction Staging Tissues Transplantation United States Work base cost insight leukemia leukemogenesis mouse model mutant novel outcome forecast prevent prognostic reconstitution response therapeutic target treatment strategy tumorigenesis ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Cell cycle checkpoints are implemented to safeguard our genome and the deregulation of which contributes to the pathogenesis of human cancers. Hence, it is of paramount importance to discover and interrogate novel key constituents of the mammalian DNA damage response network. Among G1-, S-, G2- and M-phase checkpoints, genetic studies indicate the essence of an intact S-phase checkpoint in maintaining genome integrity. Although basic framework of the S-phase checkpoint in multi-cellular organisms has been outlined, the mechanistic details remain to be elucidated. Human chromosome band 11q23 translocation disrupting the MLL gene results in poor prognostic leukemias that carry pathognomonic MLL fusions. MLL is a transcription co-activator that is best known to maintain HOX gene expression. The importance of HOXA gene deregulation in MLL leukemogenesis has been intensively investigated. However, physiological murine MLL leukemia knockin models indicated that MLL fusion-induced HOXA gene aberration alone is insufficient to initiate MLL leukemia. Therefore, further dysregulation must exit and contribute to the ultimate leukemia phenotype. Our recent studies demonstrated a close relationship between MLL and the regulation of mammalian cell cycle. MLL not only assists in the G1/S and G2/M phase transition during a normal cell division cycle but also executes the S-phase checkpoint upon DNA damage. We found that (1) MLL functions as a key effector of ATR-mediated S-phase checkpoint response, (2) activated ATR phosphorylates and thus stabilizes MLL, (3) upon checkpoint activation MLL accumulates at the late replication origin, methylates histone H3K4, and thus delays DNA replication, (4) MLL deficient cells exhibit defects in the S-phase checkpoint response, and (5) MLL fusions work as dominant negative mutants that compromise the integrity of S-phase checkpoint. Here we will determine the mechanisms by which MLL executes the S phase checkpoint response and examine whether and to what extent an S-phase checkpoint dysfunction contributes to MLL leukemogenesis. Our proposal connects MLL/MLL fusions to the S-phase checkpoint response network, which not only provides novel insights into the mammalian cell cycle checkpoint control but also shed light on the pathogenesis of poor prognostic human leukemias. PUBLIC HEALTH RELEVANCE: Cancer is a public health issue that directly impacts millions of lives and costs billions of dollars in the United States each year. Through a better understanding of the molecular pathogenesis of cancer, targeted therapeutics may be developed and eventually benefit advanced- stage cancer patients (1-2). Mixed lineage leukemia, resulted from chromosome translocation of the MLL gene, portends poor prognosis (3-6). Consequently, novel treatment strategies for this dreadful illness are urgently needed. My laboratory over the years has helped elucidate novel regulations and functions of the MLL protein (7-14). Cell cycle checkpoints safeguard our genome and compromised checkpoints contribute to the evolution of human cancer (15-18). Hence, we are particularly excited about our recent studies that link MLL to the DNA damage response network (14). Based on these findings, we propose to further investigate how MLL regulates the S-phase checkpoint and determine whether checkpoint dysfunction contributes to the MLL leukemogenesis. Data obtained from this current grant expect to provide novel insights concerning the mammalian DNA damage response network and shed light on the molecular pathogenesis of MLL leukemias.

描述（由申请人提供）：实施细胞周期检查点以保护我们的基因组，并导致其导致人类癌症的发病机理。因此，发现和审问哺乳动物DNA损伤反应网络的新型关键成分至关重要。在G1，S-，G2和M期检查点中，遗传研究表明了完整的S期检查点在维持基因组完整性方面的本质。尽管已经概述了多细胞生物中S相检查点的基本框架，但机械细节仍有待阐明。人类染色体条带11q23易位破坏了MLL基因会导致预后性白血病差，携带病情的MLL融合。 MLL是一种转录共激活因子，最著名的是维持HOX基因表达。 HOXA基因放松管制在MLL白血病发生中的重要性已得到深入研究。然而，生理鼠MLL白血病敲除模型表明，仅MLL融合诱导的HOXA基因像差仅不足以启动MLL白血病。因此，进一步的失调必须退出并有助于最终的白血病表型。我们最近的研究表明，MLL与哺乳动物细胞周期的调节之间存在密切的关系。 MLL不仅有助于正常细胞分裂周期中的G1/S和G2/M相变，而且在DNA损伤时执行S相检查点。 We found that (1) MLL functions as a key effector of ATR-mediated S-phase checkpoint response, (2) activated ATR phosphorylates and thus stabilizes MLL, (3) upon checkpoint activation MLL accumulates at the late replication origin, methylates histone H3K4, and thus delays DNA replication, (4) MLL deficient cells exhibit defects in the S-phase checkpoint response, and (5) MLL融合是损害S期检查点完整性的主要负突变体。在这里，我们将确定MLL执行S相检查点响应的机制，并检查S期检查点功能障碍是否有助于MLL白血病发生。我们的建议将MLL/MLL融合连接到S期检查点响应网络，该网络不仅提供了对哺乳动物细胞周期检查点控制的新见解，而且还阐明了预后人类白血病的发病机理。公共卫生相关性：癌症是一个公共卫生问题，每年直接影响美国数百万美元的生活和成本数十亿美元。通过更好地了解癌症的分子发病机理，可以开发靶向治疗剂，并最终使晚期癌症患者受益（1-2）。混合谱系白血病是由MLL基因的染色体易位引起的，预示着预后不良（3-6）。因此，迫切需要针对这种可怕疾病的新型治疗策略。多年来，我的实验室有助于阐明了MLL蛋白的新法规和功能（7-14）。细胞周期检查点保护了我们的基因组和损害检查点有助于人类癌症的进化（15-18）。因此，我们对将MLL与DNA损伤响应网络联系起来的最近研究感到特别兴奋（14）。基于这些发现，我们建议进一步研究MLL如何调节S期检查点，并确定检查点功能障碍是否有助于MLL白血病发生。从本目前的赠款中获得的数据期望提供有关哺乳动物DNA损伤反应网络的新见解，并阐明了MLL白血病的分子发病机理。