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.

项目摘要本质上受干扰蛋白脑膜瘤1（MN1）的高表达在AML中很常见，并与预后不良有关。 MN1在鼠造血中的强迫表达祖细胞会影响侵略性白血病。我们最近发现主要互动 MN1的合作伙伴是BAF核置位复合物。 MN1在染色质上稳定BAF。 MN1结合与调节A的增强子处的持续活性增强剂染色质有关造血茎/祖细胞计划。有趣的是，MN1的整个编码框架都是无序的。我们假设MN1通过增加多个多数 Valent，低亲和力相互作用，导致局部浓度高的BAF和早期造血转录因子。更好地了解MN1如何引起白血病可能在常规AML失败的患者人群中确定目标疗法的机会治疗。