IDP mediated transcriptional stabilization as a cause of AML

IDP 介导的转录稳定是 AML 的一个原因

基本信息

批准号：
10588195
负责人：
KATHRIN M BERNT
金额：
$ 38.13万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10588195
关键词：
Acute Myelocytic Leukemia Affect Affinity Amino Acid Sequence Amino Acids Androgen Receptor Binding Cells Cessation of life Chromatin Code Complex Disease Dose EWS-FLI1 fusion protein Enhancers Epigenetic Process Estrogen Receptors Ewings sarcoma Frequencies Gene Expression Regulation Genes Genetic Transcription Hematopoietic Hematopoietic stem cells Innovative Therapy Kinetics Leukemic Cell Liquid substance Malignant - descriptor Malignant Neoplasms Mediating Membrane Meningioma-1 Microscopy Modeling Mus Mutation Myelogenous NOTCH1 gene Nephroblastoma Nerve Degeneration Nuclear Nucleosomes Oncogenes Oncogenic Organelles Outcome Patients Peptides Phase Transition Physical condensation Physiological Positioning Attribute Prognosis Property Proteins Regulator Genes Reporting Series Site Stretching Structure System Testing Theoretical model Therapeutic Variant experimental study inhibitor insight leukemia leukemia treatment loss of function member notch protein novel strategies novel therapeutics overexpression patient population physical property polyglutamine preservation progenitor programs promoter recruit stem stem cells targeted treatment transcription factor tumorigenesis

项目摘要

PROJECT SUMMARY High expression of the intrinsically disordered protein Meningioma-1 (MN1) is common in AML, and associated with a poor prognosis. Forced expression of MN1 in murine hematopoietic progenitors induces an aggressive leukemia. We recently discovered that the primary interaction partner of MN1 is the BAF nucleosome-positioning complex. MN1 stabilizes BAF on chromatin. MN1 binding is associated with sustained active enhancer chromatin at enhancers regulating a hematopoietic stem/progenitor program. Intriguingly, MN1’s entire coding frame is disordered. We hypothesize that MN1 causes AML by overstabilizing transcriptional hubs by increasing multi- valent, low affinity interactions that result in high local concentrations of BAF and early hematopoietic transcription factors. A better understanding of how MN1 causes leukemia may identify opportunities for targeted therapies in a patient population who is failing conventional AML therapy.

项目概要本质上紊乱的蛋白 Meningioma-1 (MN1) 高表达在 AML 中很常见，并与小鼠造血系统中 MN1 的强制表达相关。我们最近发现主要的相互作用是诱发侵袭性白血病。 MN1 的伴侣是 BAF 核小体定位复合物，MN1 可稳定染色质上的 BAF。 MN1 结合与调节增强子的持续活性增强子染色质相关有趣的是，MN1 的整个编码框架是混乱的。研究发现 MN1 通过增加多基因转录中心的过度稳定而导致 AML 价、低亲和力相互作用导致 BAF 局部浓度高，并且早期更好地了解 MN1 如何导致白血病。确定对传统 AML 失败的患者群体进行靶向治疗的机会治疗。